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BIOCHEMISTRY (231 journals)                  1 2 | Last

Showing 1 - 200 of 231 Journals sorted alphabetically
AAPS PharmSciTech     Hybrid Journal   (Followers: 7)
Acetic Acid Bacteria     Open Access   (Followers: 2)
ACS Central Science     Open Access   (Followers: 6)
ACS Chemical Biology     Full-text available via subscription   (Followers: 219)
ACS Chemical Neuroscience     Full-text available via subscription   (Followers: 17)
Acta Crystallographica Section D : Biological Crystallography     Hybrid Journal   (Followers: 8)
Acta Crystallographica Section F: Structural Biology Communications     Hybrid Journal   (Followers: 7)
Advances and Applications in Bioinformatics and Chemistry     Open Access   (Followers: 9)
Advances in Biological Chemistry     Open Access   (Followers: 7)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 8)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 17)
African Journal of Biochemistry Research     Open Access   (Followers: 1)
African Journal of Chemical Education     Open Access   (Followers: 2)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 3)
American Journal of Biochemistry     Open Access   (Followers: 8)
American Journal of Biochemistry and Biotechnology     Open Access   (Followers: 65)
American Journal of Biochemistry and Molecular Biology     Open Access   (Followers: 14)
American Journal of Polymer Science     Open Access   (Followers: 25)
Amino Acids     Hybrid Journal   (Followers: 7)
Analytical Biochemistry     Hybrid Journal   (Followers: 153)
Angiogenesis     Hybrid Journal   (Followers: 3)
Annals of Clinical Biochemistry     Hybrid Journal   (Followers: 7)
Annual Review of Biochemistry     Full-text available via subscription   (Followers: 52)
Annual Review of Chemical and Biomolecular Engineering     Full-text available via subscription   (Followers: 12)
Applied Biochemistry and Biotechnology     Hybrid Journal   (Followers: 44)
Applied Biochemistry and Microbiology     Hybrid Journal   (Followers: 17)
Applied Organometallic Chemistry     Hybrid Journal   (Followers: 6)
Archives of Biochemistry and Biophysics     Hybrid Journal   (Followers: 19)
Archives of Insect Biochemistry and Physiology     Hybrid Journal  
Archives Of Physiology And Biochemistry     Hybrid Journal   (Followers: 1)
Asian Journal of Biochemistry     Open Access   (Followers: 1)
Avicenna Journal of Medical Biochemistry     Open Access  
Bangladesh Journal of Medical Biochemistry     Open Access   (Followers: 2)
BBA Clinical     Open Access  
BBR : Biochemistry and Biotechnology Reports     Open Access   (Followers: 4)
Biocatalysis     Open Access  
Biochemical and Biophysical Research Communications     Hybrid Journal   (Followers: 20)
Biochemical and Molecular Medicine     Full-text available via subscription   (Followers: 4)
Biochemical Compounds     Open Access  
Biochemical Engineering Journal     Hybrid Journal   (Followers: 15)
Biochemical Genetics     Hybrid Journal   (Followers: 3)
Biochemical Journal     Full-text available via subscription   (Followers: 25)
Biochemical Pharmacology     Hybrid Journal   (Followers: 9)
Biochemical Society Transactions     Full-text available via subscription   (Followers: 4)
Biochemical Systematics and Ecology     Hybrid Journal   (Followers: 3)
Biochemistry     Full-text available via subscription   (Followers: 267)
Biochemistry & Pharmacology : Open Access     Open Access   (Followers: 3)
Biochemistry & Physiology : Open Access     Open Access  
Biochemistry (Moscow)     Hybrid Journal   (Followers: 4)
Biochemistry (Moscow) Supplement Series A: Membrane and Cell Biology     Hybrid Journal   (Followers: 3)
Biochemistry (Moscow) Supplemental Series B: Biomedical Chemistry     Hybrid Journal   (Followers: 3)
Biochemistry and Biophysics Reports     Open Access  
Biochemistry and Cell Biology     Full-text available via subscription   (Followers: 14)
Biochemistry and Molecular Biology Education     Hybrid Journal   (Followers: 6)
Biochemistry and Molecular Biology of Fishes     Full-text available via subscription   (Followers: 1)
Biochemistry Research International     Open Access   (Followers: 6)
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids     Hybrid Journal   (Followers: 7)
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease     Hybrid Journal   (Followers: 13)
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research     Hybrid Journal   (Followers: 7)
Biochimie     Hybrid Journal   (Followers: 7)
Biochimie Open     Open Access  
Bioconjugate Chemistry     Full-text available via subscription   (Followers: 28)
BioDrugs     Full-text available via subscription   (Followers: 7)
Bioelectrochemistry     Hybrid Journal   (Followers: 2)
Biofuels     Hybrid Journal   (Followers: 10)
Biogeochemistry     Hybrid Journal   (Followers: 13)
BioInorganic Reaction Mechanisms     Hybrid Journal   (Followers: 1)
Biokemistri     Open Access  
Biological Chemistry     Partially Free   (Followers: 24)
Biomaterials Research     Open Access   (Followers: 4)
Biomedicines     Open Access   (Followers: 1)
BioMolecular Concepts     Hybrid Journal   (Followers: 2)
Bioscience, Biotechnology, and Biochemistry     Hybrid Journal   (Followers: 24)
Biosimilars     Open Access   (Followers: 1)
Biotechnology and Applied Biochemistry     Hybrid Journal   (Followers: 45)
Bitácora Digital     Open Access  
BMC Biochemistry     Open Access   (Followers: 14)
Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca : Food Science and Technology     Open Access  
Carbohydrate Polymers     Hybrid Journal   (Followers: 8)
Cell Biochemistry and Biophysics     Hybrid Journal   (Followers: 6)
Cell Biochemistry and Function     Hybrid Journal   (Followers: 6)
Cellular Physiology and Biochemistry     Open Access   (Followers: 3)
ChemBioChem     Hybrid Journal   (Followers: 5)
Chemical and Biological Technologies for Agriculture     Open Access  
Chemical Biology & Drug Design     Hybrid Journal   (Followers: 20)
Chemical Engineering Journal     Hybrid Journal   (Followers: 33)
Chemical Senses     Hybrid Journal   (Followers: 1)
Chemical Speciation and Bioavailability     Open Access   (Followers: 1)
Chemico-Biological Interactions     Hybrid Journal   (Followers: 3)
Chemistry & Biodiversity     Hybrid Journal   (Followers: 6)
Chemistry & Biology     Full-text available via subscription   (Followers: 30)
Chemistry and Ecology     Hybrid Journal  
ChemTexts     Hybrid Journal  
Clinica Chimica Acta     Hybrid Journal   (Followers: 33)
Clinical Biochemist Reviews     Full-text available via subscription   (Followers: 1)
Clinical Biochemistry     Hybrid Journal   (Followers: 18)
Clinical Chemistry     Full-text available via subscription   (Followers: 67)
Clinical Chemistry and Laboratory Medicine     Hybrid Journal   (Followers: 59)
Clinical Lipidology     Full-text available via subscription   (Followers: 1)
Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology     Hybrid Journal   (Followers: 5)
Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 2)
Comparative Biochemistry and Physiology Part C: Toxicology & Pharmacology     Hybrid Journal   (Followers: 7)
Comparative Biochemistry and Physiology Part D: Genomics and Proteomics     Hybrid Journal   (Followers: 3)
Comprehensive Biochemistry     Full-text available via subscription   (Followers: 1)
Computational Biology and Chemistry     Hybrid Journal   (Followers: 12)
Critical Reviews in Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 5)
Current Chemical Biology     Hybrid Journal   (Followers: 2)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 15)
Current Opinion in Chemical Biology     Hybrid Journal   (Followers: 25)
Current Opinion in Lipidology     Hybrid Journal   (Followers: 6)
DNA Barcodes     Open Access  
Doklady Biochemistry and Biophysics     Hybrid Journal   (Followers: 1)
Doklady Chemistry     Hybrid Journal  
Egyptian Journal of Biochemistry and Molecular Biology     Full-text available via subscription  
FABICIB     Open Access  
FEBS Letters     Hybrid Journal   (Followers: 56)
FEBS Open Bio     Open Access   (Followers: 3)
Fish Physiology and Biochemistry     Hybrid Journal   (Followers: 4)
Food & Function     Full-text available via subscription   (Followers: 5)
Foundations of Modern Biochemistry     Full-text available via subscription  
Free Radicals and Antioxidants     Full-text available via subscription   (Followers: 4)
Frontiers in Molecular Biosciences     Open Access   (Followers: 2)
Frontiers in Natural Product Chemistry     Hybrid Journal  
Global Biogeochemical Cycles     Full-text available via subscription   (Followers: 15)
Green Chemistry     Full-text available via subscription   (Followers: 9)
Histochemistry and Cell Biology     Hybrid Journal   (Followers: 4)
Indian Journal of Biochemistry and Biophysics (IJBB)     Open Access   (Followers: 3)
Indian Journal of Clinical Biochemistry     Hybrid Journal   (Followers: 1)
Indonesian Biomedical Journal     Open Access  
Insect Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 3)
International Journal of Biochemistry & Cell Biology     Hybrid Journal   (Followers: 7)
International Journal of Biochemistry and Biophysics     Open Access   (Followers: 1)
International Journal of Biological Chemistry     Open Access   (Followers: 4)
International Journal of Biomedical Nanoscience and Nanotechnology     Hybrid Journal   (Followers: 6)
International Journal of Food Contamination     Open Access  
International Journal of Plant Physiology and Biochemistry     Open Access   (Followers: 1)
International Journal of Plant Research     Open Access   (Followers: 3)
International Journal of Secondary Metabolite     Open Access   (Followers: 1)
Invertebrate Immunity     Open Access   (Followers: 1)
JBIC Journal of Biological Inorganic Chemistry     Hybrid Journal   (Followers: 5)
Journal of Microbial & Biochemical Technology     Open Access   (Followers: 2)
Journal of Applied Biology & Biotechnology     Open Access   (Followers: 2)
Journal of Bioactive and Compatible Polymers     Hybrid Journal   (Followers: 2)
Journal of Biochemistry     Hybrid Journal   (Followers: 44)
Journal of Biological Chemistry     Full-text available via subscription   (Followers: 187)
Journal of Biomaterials Science, Polymer Edition     Hybrid Journal   (Followers: 9)
Journal of Carbohydrate Chemistry     Hybrid Journal   (Followers: 7)
Journal of Cellular Biochemistry     Hybrid Journal   (Followers: 5)
Journal of Chemical Biology     Hybrid Journal   (Followers: 1)
Journal of Chemical Neuroanatomy     Hybrid Journal  
Journal of Clinical Lipidology     Hybrid Journal   (Followers: 1)
Journal of Comparative Physiology B : Biochemical, Systemic, and Environmental Physiology     Hybrid Journal   (Followers: 4)
Journal of Drug Discovery and Therapeutics     Open Access  
Journal of Enzyme Inhibition and Medicinal Chemistry     Hybrid Journal   (Followers: 3)
Journal of Evolutionary Biochemistry and Physiology     Hybrid Journal  
Journal of Food and Drug Analysis     Open Access  
Journal of Forensic Toxicology and Pharmacology     Hybrid Journal   (Followers: 3)
Journal of Inborn Errors of Metabolism and Screening     Open Access  
Journal of Inorganic Biochemistry     Hybrid Journal   (Followers: 6)
Journal of Medical and Biomedical Sciences     Open Access  
Journal of Medical Biochemistry     Open Access   (Followers: 4)
Journal of Medicine and Biomedical Research     Open Access   (Followers: 1)
Journal of Molecular Biochemistry     Open Access   (Followers: 3)
Journal of Molecular Diagnostics     Hybrid Journal   (Followers: 7)
Journal of Neurochemistry     Hybrid Journal   (Followers: 3)
Journal of Nutritional Biochemistry     Hybrid Journal   (Followers: 7)
Journal of Pediatric Biochemistry     Hybrid Journal   (Followers: 1)
Journal of Peptide Science     Hybrid Journal   (Followers: 22)
Journal of Photochemistry and Photobiology B: Biology     Hybrid Journal   (Followers: 3)
Journal of Physiobiochemical Metabolism     Hybrid Journal   (Followers: 1)
Journal of Physiology and Biochemistry     Hybrid Journal   (Followers: 3)
Journal of Plant Biochemistry and Biotechnology     Hybrid Journal   (Followers: 6)
Journal of Steroid Biochemistry and Molecular Biology     Hybrid Journal   (Followers: 2)
Journal of Virology & Antiviral Research     Hybrid Journal   (Followers: 5)
Journal of Wood Chemistry and Technology     Hybrid Journal   (Followers: 7)
La Rivista Italiana della Medicina di Laboratorio - Italian Journal of Laboratory Medicine     Hybrid Journal  
Lab on a Chip     Full-text available via subscription   (Followers: 34)
Marine Chemistry     Hybrid Journal   (Followers: 6)
Methods in Enzymology     Full-text available via subscription   (Followers: 11)
Molecular and Biochemical Parasitology     Hybrid Journal   (Followers: 2)
Molecular and Cellular Biochemistry     Hybrid Journal   (Followers: 5)
Molecular Aspects of Medicine     Hybrid Journal   (Followers: 3)
Molecular Informatics     Hybrid Journal   (Followers: 6)
Molecular inhibitors in targeted therapy     Open Access  
Moscow University Chemistry Bulletin     Hybrid Journal   (Followers: 1)
Mycology : An International Journal on Fungal Biology     Hybrid Journal   (Followers: 6)
Natural Products and Bioprospecting     Open Access   (Followers: 3)
Nature Chemical Biology     Full-text available via subscription   (Followers: 70)
Nature Communications     Open Access   (Followers: 162)
Neurosignals     Open Access  
NOVA     Open Access  
Novelty in Biomedicine     Open Access  
OA Biochemistry     Open Access   (Followers: 1)
OA Inflammation     Open Access  
Ocean Acidification     Open Access   (Followers: 3)
Organic & Biomolecular Chemistry     Full-text available via subscription   (Followers: 86)
Peptidomics     Open Access  
Pesticide Biochemistry and Physiology     Hybrid Journal   (Followers: 4)
Pflugers Archiv European Journal of Physiology     Hybrid Journal   (Followers: 3)

        1 2 | Last

Journal Cover Archives of Biochemistry and Biophysics
  [SJR: 1.478]   [H-I: 138]   [19 followers]  Follow
   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0003-9861 - ISSN (Online) 1096-0384
   Published by Elsevier Homepage  [3031 journals]
  • Antimicrobial mechanism of epigallocatechin gallate and gallocatechin
           gallate: They target 1-deoxy-d-xylulose 5-phosphate reductoisomerase, the
           key enzyme of the MEP terpenoid biosynthetic pathway
    • Authors: Xian Hui; Shui-Hong Hua; Qian-Qian Wu; Heng Li; Wen-Yun Gao
      Pages: 1 - 8
      Abstract: Publication date: 15 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 622
      Author(s): Xian Hui, Shui-Hong Hua, Qian-Qian Wu, Heng Li, Wen-Yun Gao
      The catechins EGCG and GCG show a variety of pharmacological activities, especially an antibacterial capacity, but their modes of antimicrobial action have not been fully elucidated. 1-Deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), the first key enzyme in the MEP pathway for terpenoid biosynthesis, is a recently validated antimicrobial target. In order to disclose the antibacterial mechanism of EGCG and GCG, the DXR inhibitory activity of them was investigated in this study. The data show that EGCG and GCG both could specifically suppress the activity of DXR, with EGCG exhibiting relatively low effect against DXR (IC50 about 210 μM) and GCG displaying strong activity (IC50 27.5 μM). In addition, studies on inhibition kinetics of the catechins against DXR demonstrate that they are competitive inhibitors of DXR against DXP and uncompetitive inhibitors with respect to NADPH. Meanwhile, the possible interactions between DXR and the catechine, esyth onlols were simulated via docking experiments.
      Graphical abstract image

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 622 (2017)
  • Tyrosine oxidation and nitration in transmembrane peptides is connected to
           lipid peroxidation
    • Authors: Silvina Bartesaghi; Daniel Herrera; Débora M. Martinez; Ariel Petruk; Verónica Demicheli; Madia Trujillo; Marcelo A. Martí; Darío A. Estrín; Rafael Radi
      Pages: 9 - 25
      Abstract: Publication date: Available online 13 April 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Silvina Bartesaghminni, Daniel Herrera, Débora M. Martinez, Ariel Petruk, Verónica Demicheli, Madia Trujillo, Marcelo A. Martí, Darío A. Estrín, Rafael Radi
      Tyrosine nitration is an oxidative post-translational modification that can occur in proteins associated to hydrophobic bio-structures such as membranes and lipoproteins. In this work, we have studied tyrosine nitration in membranes using a model system consisting of phosphatidylcholine liposomes with pre-incorporated tyrosine-containing 23 amino acid transmembrane peptides. Tyrosine residues were located at positions 4, 8 or 12 of the amino terminal, resulting in different depths in the bilayer. Tyrosine nitration was accomplished by exposure to peroxynitrite and a peroxyl radical donor or hemin in the presence of nitrite. In egg yolk phosphatidylcholine liposomes, nitration was highest for the peptide with tyrosine at position 8 and dramatically increased as a function of oxygen levels. Molecular dynamics studies support that the proximity of the tyrosine phenolic ring to the linoleic acid peroxyl radicals contributes to the efficiency of tyrosine oxidation. In turn, α-tocopherol inhibited both lipid peroxidation and tyrosine nitration. The mechanism of tyrosine nitration involves a “connecting reaction” by which lipid peroxyl radicals oxidize tyrosine to tyrosyl radical and was fully recapitulated by computer-assisted kinetic simulations. Altogether, this work underscores unique characteristics of the tyrosine oxidation and nitration process in lipid-rich milieu that is fueled via the lipid peroxidation process.
      Graphical abstract image

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 622 (2017)
  • MsrB3 deficiency induces cancer cell apoptosis through p53-independent and
           ER stress-dependent pathways
    • Authors: Geun-Hee Kwak; Hwa-Young Kim
      Pages: 1 - 5
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Geun-Hee Kwak, Hwa-Young Kim
      We have previously shown that down-regulation of methionine sulfoxide reductase B3 (MsrB3) induces cancer cell apoptosis through the activation of the intrinsic mitochondrial pathway. However, the mechanism through which MsrB3 deficiency results in cancer cell death is poorly understood. In this study, we investigated whether p53 and endoplasmic reticulum (ER) stress are involved in MsrB3 deficiency-induced cancer cell apoptosis using breast and colon cancer cells. MsrB3 depletion resulted in p53 down-regulation at the post-transcriptional level. MsrB3 deficiency induced cell death to a similar extent in both p53 wild-type (p53 +/+) and null (p53 −/−) cancer cells, suggesting that MsrB3 deficiency-induced apoptosis occurs independently of p53. MsrB3 deficiency significantly increased ER stress, which resulted in apoptosis. In addition, MsrB3 depletion activated the pro-apoptotic Bim molecule, which is essential for ER stress-induced apoptosis. MsrB3 deficiency increased cytosolic calcium levels, suggesting that MsrB3 down-regulation leads to a disturbance of calcium homeostasis in the ER, which consequently triggers ER stress. MsrB3 overexpression in MsrB3-depleted cells reduced ER stress, and was accompanied by at least partial recovery of cell viability. Taken together, our results suggest that MsrB3 plays a critical role in cancer cell apoptosis through the modulation of ER stress status.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 621 (2017)
  • Structural insights into the activation mechanisms of human HtrA serine
    • Authors: Dorota Zurawa-Janicka; Tomasz Wenta; Miroslaw Jarzab; Joanna Skorko-Glonek; Przemyslaw Glaza; Artur Gieldon; Jerzy Ciarkowski; Barbara Lipinska
      Pages: 6 - 23
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Dorota Zurawa-Janicka, Tomasz Wenta, Miroslaw Jarzab, Joanna Skorko-Glonek, Przemyslaw Glaza, Artur Gieldon, Jerzy Ciarkowski, Barbara Lipinska
      Human HtrA1-4 proteins belong to the HtrA family of evolutionarily conserved serine proteases and function as important modulators of many physiological processes, including maintenance of mitochondrial homeostasis, cell signaling and apoptosis. Disturbances in their action are linked to severe diseases, including oncogenesis and neurodegeneration. The HtrA1-4 proteins share structural and functional features of other members of the HtrA protein family, however there are several significant differences in structural architecture and mechanisms of action which makes each of them unique. Our goal is to present recent studies regarding human HtrAs. We focus on their physiological functions, structure and regulation, and describe current models of activation mechanisms. Knowledge of molecular basis of the human HtrAs' action is a subject of great interest; it is crucial for understanding their relevance in cellular physiology and pathogenesis as well as for using them as targets in future therapies of diseases such as neurodegenerative disorders and cancer.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 621 (2017)
  • N-acetylcysteine improves the quality of red blood cells stored for
    • Authors: Florencia Amen; Andrea Machin; Cristina Touriño; Ismael Rodríguez; Ana Denicola; Leonor Thomson
      Pages: 31 - 37
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Florencia Amen, Andrea Machin, Cristina Touriño, Ismael Rodríguez, Ana Denicola, Leonor Thomson
      Storage inflicts a series of changes on red blood cells (RBC) that compromise the cell survival and functionality; largely these alterations (storage lesions) are due to oxidative modifications. The possibility of improving the quality of packed RBC stored for transfusion including N-acetylcysteine (NAC) in the preservation solution was explored. Relatively high concentrations of NAC (20–25 mM) were necessary to prevent the progressive leakage of hemoglobin, while lower concentrations (≥2.5 mM) were enough to prevent the loss of reduced glutathione during the first 21 days of storage. Peroxiredoxin-2 was also affected during storage, with a progressive accumulation of disulfide-linked dimers and hetero-protein complexes in the cytosol and also in the membrane of stored RBC. Although the presence of NAC in the storage solution was unable to avoid the formation of thiol-mediated protein complexes, it partially restored the capacity of the cell to metabolize H2O2, indicating the potential use of NAC as an additive in the preservation solution to improve RBC performance after transfusion.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 621 (2017)
  • FBXO25 regulates MAPK signaling pathway through inhibition of ERK1/2
    • Authors: Felipe R. Teixeira; Adriana O. Manfiolli; Nichelle A. Vieira; Ana Carla Medeiros; Priscila de O. Coelho; Dimitrius Santiago Guimarães; Deborah Schechtman; Marcelo D. Gomes
      Pages: 38 - 45
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Felipe R. Teixeira, Adriana O. Manfiolli, Nichelle A. Vieira, Ana Carla Medeiros, Priscila de O. Coelho, Dimitrius Santiago Guimarães, Deborah Schechtman, Marcelo D. Gomes
      The FBXO25 mediates degradation of ELK-1 and thus inhibits transcriptional activation of immediate early genes (iEG). Here we show that FBXO25 regulates yet another node of this signaling pathway, by decreasing MAPK/ERK activity. We show that induction of FBXO25 reduced ERK1/2 phosphorylation independently of MEK1/2. Accordingly, in HAP1 FBXO25 knockout cells (FBXO25KO), we observed that upon PMA treatment ERK1/2 was more active than in parental cells. An increase in cell proliferation under receptor mediated activation of the ERK signaling pathway in FBXO25KO cells was also observed. Taken together we show that FBXO25 functions as a negative regulator of MAPK signaling though the reduction of ERK1/2 activation.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 621 (2017)
  • Ascorbic acid inhibits human insulin aggregation and protects against
           amyloid induced cytotoxicity
    • Authors: Parvez Alam; Ayesha Zainab Beg; Mohammad Khursheed Siddiqi; Sumit Kumar Chaturvedi; Ravi Kant Rajpoot; Mohd Rehan Ajmal; Masihuz Zaman; Ali S. Abdelhameed; Rizwan Hasan Khan
      Pages: 54 - 62
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Parvez Alam, Ayesha Zainab Beg, Mohammad Khursheed Siddiqi, Sumit Kumar Chaturvedi, Ravi Kant Rajpoot, Mohd Rehan Ajmal, Masihuz Zaman, Ali S. Abdelhameed, Rizwan Hasan Khan
      Protein aggregation into oligomers and fibrils are associated with many human pathophysiologies. Compounds that modulate protein aggregation and interact with preformed fibrils and convert them to less toxic species, expect to serve as promising drug candidates and aid to the drug development efforts against aggregation diseases. In present study, the kinetics of amyloid fibril formation by human insulin (HI) and the anti-amyloidogenic activity of ascorbic acid (AA) were investigated by employing various spectroscopic, imaging and computational approaches. We demonstrate that ascorbic acid significantly inhibits the fibrillation of HI in a dose-dependent manner. Interestingly ascorbic acid destabilise the preformed amyloid fibrils and protects human neuroblastoma cell line (SH- SY5Y) against amyloid induced cytotoxicity. The present data signifies the role of ascorbic acid that can serve as potential molecule in preventing human insulin aggregation and associated pathophysiologies.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 621 (2017)
  • Metabolites of 2,3-diketogulonate delay peroxidase action and induce
           non-enzymic H2O2 generation: Potential roles in the plant cell wall
    • Authors: Anna Kärkönen; Rebecca A. Dewhirst; C. Logan Mackay; Stephen C. Fry
      Pages: 12 - 22
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Anna Kärkönen, Rebecca A. Dewhirst, C. Logan Mackay, Stephen C. Fry
      A proportion of the plant's l-ascorbate (vitamin C) occurs in the apoplast, where it and its metabolites may act as pro-oxidants and anti-oxidants. One ascorbate metabolite is 2,3-diketogulonate (DKG), preparations of which can non-enzymically generate H2O2 and delay peroxidase action on aromatic substrates. As DKG itself generates several by-products, we characterised these and their ability to generate H2O2 and delay peroxidase action. DKG preparations rapidly produced a by-product, compound (1), with λ max 271 and 251 nm at neutral and acidic pH respectively. On HPLC, (1) co-eluted with the major H2O2-generating and peroxidase-delaying principle. Compound (1) was slowly destroyed by ascorbate oxidase, and was less stable at pH 6 than at pH 1. Electrophoresis of an HPLC-enriched preparation of (1) suggested a strongly acidic (pK a ≈ 2.3) compound. Mass spectrometry suggested that un-ionised (1) has the formula C6H6O5, i.e. it is a reduction product of DKG (C6H8O7). In conclusion, compound (1) is the major H2O2-generating, peroxidase-delaying principle formed non-enzymically from DKG in the pathway ascorbate → dehydroascorbic acid → DKG → (1). We hypothesise that (1) generates apoplastic H2O2 (and consequently hydroxyl radicals) and delays cell-wall crosslinking — both these effects favouring wall loosening, and possibly playing a role in pathogen defence.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • Effect of genetic polymorphism on the inhibition of dopamine formation
           from p-tyramine catalyzed by brain cytochrome P450 2D6
    • Authors: Toshiro Niwa; Marina Shizuku; Kaori Yamano
      Pages: 23 - 27
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Toshiro Niwa, Marina Shizuku, Kaori Yamano
      The inhibitory effects of steroid hormones, including glucocorticoids such as cortisol, and related compounds on dopamine formation from p-tyramine, catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr) were compared with the effects of those catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. Inhibition constants (K i) or 50% inhibitory concentrations of six steroid hormones (cortisol, cortisone, corticosterone, dehydroepiandrosterone, progesterone, and pregnenolone) and quinidine and quinine—typical potent inhibitors of the human CYP2D6 and rat CYP2D subfamily, respectively—toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10 expressed in recombinant Escherichia coli were compared. Although most steroid hormones had no or minor inhibitory effects on the dopamine formation by all CYP2D6 variants, progesterone inhibited the metabolism and K i value against CYP2D6.10 was approximately twice that for CYP2D6.1 and CYP2D6.2. Quinidine exhibited stronger inhibition than quinine; however, these two compounds inhibited the CYP2D6.10-mediated reaction more weakly than the CYP2D6.1 and CYP2D6.2 reactions. These results suggest that CYP2D6 polymorphism would affect drug interaction through dopamine formation in the brain.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • Phosphoethanolamine addition to the Heptose I of the Lipopolysaccharide
           modifies the inner core structure and has an impact on the binding of
           Polymyxin B to the Escherichia coli outer membrane
    • Authors: Javier Salazar; Mackarenna Alarcón; Jaime Huerta; Belén Navarro; Daniel Aguayo
      Pages: 28 - 34
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Javier Salazar, Mackarenna Alarcón, Jaime Huerta, Belén Navarro, Daniel Aguayo
      Phosphoethanolamine (pEtN) decoration of E. coli Lipopolysaccharide (LPS) provides resistance to the antimicrobial Polymyxin B (PolB). While EptA and EptB enzymes catalyze the addition of pEtN to the Lipid A and Kdo (pEtN-Kdo-Lipid A), EptC catalyzes the pEtN addition to the Heptose I (pEtN-HeptI). In this study, we investigated the contribution of pEtN-HeptI to PolB resistance using eptA/eptB and eptC deficient E. coli K12 and its wild-type parent strains. These mutations were shown to decrease the antimicrobial activity of PolB on cells grown under pEtN-addition inducing conditions. Furthermore, the 1-N-phenylnapthylamine uptake assay revealed that in vivo PolB has a reduced OM-permeabilizing activity on the ΔeptA/eptB strain compared with the ΔeptC strain. In vitro, the changes in size and zeta potential of LPS-vesicles indicate that pEtN-HeptI reduce the PolB binding, but in a minor extent than pEtN-Kdo-Lipid A. Molecular dynamics analysis revealed the structural basis of the PolB resistance promoted by pEtN-HeptI, which generate a new hydrogen-bonding networks and a denser inner core region. Altogether, the experimental and theoretical assays shown herein indicate that pEtN-HeptI addition promote an LPS conformational rearrangement, that could act as a shield by hindering the accession of PolB to inner LPS-targets moieties.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • Thermodynamics of tunnel formation upon substrate binding in a processive
           glycoside hydrolase
    • Authors: Anne Grethe Hamre; Emil Ebbestad Frøberg; Vincent G.H. Eijsink; Morten Sørlie
      Pages: 35 - 42
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Anne Grethe Hamre, Emil Ebbestad Frøberg, Vincent G.H. Eijsink, Morten Sørlie
      Glycoside hydrolases (GHs) catalyze the hydrolysis of glycosidic bonds and are key enzymes in carbohydrate metabolism. Efficient degradation of recalcitrant polysaccharides such as chitin and cellulose is accomplished due to synergistic enzyme cocktails consisting of accessory enzymes and mixtures of GHs with different modes of action and active site topologies. The substrate binding sites of chitinases and cellulases often have surface exposed aromatic amino acids and a tunnel or cleft topology. The active site of the exo-processive chitinase B (ChiB) from Serratia marcescens is partially closed, creating a tunnel-like catalytic cleft. To gain insight in the fundamental principles of substrate binding in this enzyme, we have studied the contribution of five key residues involved in substrate binding and tunnel formation to the thermodynamics of substrate binding. Mutation of Trp97, Phe190, Trp220 and Glu221, which are all part of the tunnel walls, resulted in significant less favorable conformational entropy change (ΔS°conf) upon binding (–TΔΔS°conf = ∼5 kcal/mol). This suggest that these residues are important for the structural rigidity and pre-shaping of the tunnel prior to binding. Mutation of Asp316, which, by forming a hydrogen bond to Trp97 is crucial in the active-site tunnel roof, resulted in a more favorable ΔS°conf relative to the wild type (–TΔΔS°conf = −2.2 kcal/mol). This shows that closing the tunnel-roof comes with an entropy cost, as previously suggested based on the crystal structures of GHs with tunnel topologies in complex with their substrates.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • Functional characterization of a common CYP4F11 genetic variant and
           identification of functionally defective CYP4F11 variants in erythromycin
           metabolism and 20-HETE synthesis
    • Authors: Myeongjin Yi; Sun-Ah Cho; Jungki Min; Dong Hyun Kim; Jae-Gook Shin; Su-Jun Lee
      Pages: 43 - 51
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Myeongjin Yi, Sun-Ah Cho, Jungki Min, Dong Hyun Kim, Jae-Gook Shin, Su-Jun Lee
      CYP4F11, together with CYP4F2, plays an important role in the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. We identified 21 variants by whole exome sequencing, including 4 non-synonymous variants in Korean subjects. The proteins of the wild-type CYP4F11 and the four coding variants (C276R, D315N, D374Y, and D446N) were expressed in Escherichia coli DH5α cells and purified to give cytochrome P450-specific carbon monoxide difference spectra. Wild-type CYP4F2 was also expressed and purified to compare its activity with the CYP4F11 wild-type. Wild-type CYP4F11 exhibited the highest maximal clearance for erythromycin N-demethylase activity followed by the variants D374Y, D446N, C276R, and D315N. In particular, the CYP4F11 D315N protein showed about 50% decrease in intrinsic clearance compared to the wild type. The ability of wild-type CYP4F11 and the variants to synthesize 20-HETE from arachidonic acid was similar; the CYP4F11 D315N variant, however, showed only 68% of wild-type activity. Furthermore, the ability of CYP4F2 to synthesize 20-HETE was 1.7-fold greater than that of CYP4F11. Overall, our results suggest that the metabolism of CYP4F11 substrates may be reduced in individuals carrying the CYP4F11 D315N genetic variant and individuals carrying the common D446N CYP4F11 variant likely exhibit comparable 20-HETE synthesis as individuals expressing wild-type CYP4F11.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • MicroRNA-182 aggravates cerebral ischemia injury by targeting inhibitory
           member of the ASPP family (iASPP)
    • Authors: Han Yi; Yan Huang; Fengrui Yang; Wenzhi Liu; Sheng He; Xiaoling Hu
      Pages: 52 - 58
      Abstract: Publication date: 15 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 620
      Author(s): Han Yi, Yan Huang, Fengrui Yang, Wenzhi Liu, Sheng He, Xiaoling Hu
      Ischemic stroke is one of the leading causes of death and disability globally and has been regarded as a major public health problem. MicroRNA 182 (miR-182) plays important roles in cellular differentiation, cell growth, cell apoptosis and metastasis. However, the role of miR-182 in the cerebral ischemia injury has never been investigated. In the present study, we demonstrate a crucial role of miR-182 in down-regulating inhibitory member of the ASPP family (iASPP) expression and promoting cerebral ischemia injury. MiR-182 also promotes NO and 3-NT production, and Caspase3 expression, while reduces SOD and MnSOD activities. Furthermore, the amplified cerebral ischemia injury induced by miR-182 is aggravated by inhibition of iASPP. In conclusion, miR-182 plays an aggressive role in the cerebral ischemia injury, and this is associated with inhibited iASPP expression.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 620 (2017)
  • Trifluoroethanol-induced conformational transition of the C-terminal
           sterile alpha motif (SAM) of human p73
    • Authors: José L. Neira; Ana Cámara-Artigas
      Pages: 1 - 9
      Abstract: Publication date: Available online 21 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): José L. Neira, Ana Cámara-Artigas
      The alpha splice variant of p73 (p73α), a homologue of the tumour suppressor p53, has at its C terminus a sterile alpha motif (SAM); this domain, SAMp73, is involved in lipid binding and it is thought to mediate in protein-protein interactions. As SAMp73 is a 68-residue-long helical bundle, it could be a good model to study the (2,2,2-trifluoroethanol) TFE-induced conformational transitions of α-helical proteins. Furthermore, as SAMp73 binds to lipids through a well-known polypeptide patch, we can test whether TFE is a good mimic of lipids and membranes. To address those questions, we used several biophysical probes, namely, fluorescence, circular dichroism, 1D, 2D and 3D-NMR spectroscopies, and dynamic light scattering. The TFE-induced conformational transition of SAMp73 was complex, involving several species as detected by the biophysical probes. The last TFE-induced transition occurred at a concentration of TFE of ∼20% (v/v), where the protein lost its compactness. None of those TFE-induced species accumulated during the two-state folding of SAMp73 in aqueous solution. The final state at 40% TFE was highly helical, but its structure was not rigid. For SAMp73, TFE did not properly mimic a membrane-like environment, since at very low TFE concentrations, other residues, together with those known to interact with lipids, were also affected by the co-solvent. Comparison with studies on isolated peptides, comprising the helical regions of SAMp73, suggests that peptides were good models of the intact protein in TFE.
      Graphical abstract image

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 619 (2017)
  • Thermodynamics of interactions between mammalian cytochromes P450 and b5
    • Authors: Evgeny Yablokov; Anna Florinskaya; Alexei Medvedev; Gennady Sergeev; Natallia Strushkevich; Alexander Luschik; Tatsiana Shkel; Irina Haidukevich; Andrei Gilep; Sergey Usanov; Alexis Ivanov
      Pages: 10 - 15
      Abstract: Publication date: 1 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 619
      Author(s): Evgeny Yablokov, Anna Florinskaya, Alexei Medvedev, Gennady Sergeev, Natallia Strushkevich, Alexander Luschik, Tatsiana Shkel, Irina Haidukevich, Andrei Gilep, Sergey Usanov, Alexis Ivanov
      Cytochromes P450 (CYPs) play an important role in the metabolism of xenobiotics and various endogenous substrates. Being a crucial component of the microsomal monooxygenase system, CYPs are involved in numerous protein-protein interactions. However, mechanisms underlying molecular interactions between components of the monooxygenase system still need better characterization. In this study thermodynamic parameters of paired interactions between mammalian CYPs and cytochromes b5 (CYB5) have been evaluated using a Surface Plasmon Resonance (SPR) based biosensor Biacore 3000. Analysis of 18 pairs of CYB5-CYP complexes formed by nine different isoforms of mammalian CYPs and two isoforms of human CYB5 has shown that thermodynamically these complexes can be subdivided into enthalpy-driven and entropy-driven groups. Formation of the enthalpy-driven complexes was observed in the case of microsomal CYPs allosterically regulated by CYB5 (CYB5A-CYP3A4, CYB5A-CYP3A5, CYB5A-CYP17A1). The entropy-driven complexes were formed when CYB5 had no effect on the CYP activity (CYB5A-CYP51A1, CYB5A-CYP1B1, CYB5B-CYP11A1). Results of this study suggest that such interactions determining protein clustering are indirectly linked to the monooxygenase functioning. Positive ΔH values typical for such interactions may be associated with displacement of the solvation shells of proteins upon clustering. CYB5-CYP complex formation accompanied by allosteric regulation of CYP activity by CYB5 is enthalpy-dependent.

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
      Issue No: Vol. 619 (2017)
  • Interaction mechanism of insulin-like peptide 5 with relaxin family
           peptide receptor 4
    • Authors: Meng-Jun Hu; Dian Wei; Xiao-Xia Shao; Jia-Hui Wang; Ya-Li Liu; Zeng-Guang Xu; Zhan-Yun Guo
      Pages: 27 - 34
      Abstract: Publication date: 1 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 619
      Author(s): Meng-Jun Hu, Dian Wei, Xiao-Xia Shao, Jia-Hui Wang, Ya-Li Liu, Zeng-Guang Xu, Zhan-Yun Guo
      Insulin-like peptide 5 (INSL5) is a gut peptide hormone belonging to the insulin/relaxin superfamily. It is implicated in the regulation of food intake and glucose homeostasis by activating relaxin family peptide receptor 4 (RXFP4). Previous studies have suggested that the B-chain is important for INSL5 activity against RXFP4. However, functionalities of the B-chain residues have not yet been systematically studied. In the present work, we conducted alanine-scanning mutagenesis of the B-chain residues of human INSL5 to obtain an overview of their contributions. Binding and activation assays of these INSL5 mutants with human RXFP4 identified two essential exposed B-chain C-terminal residues (B23Arg and B24Trp) and one important exposed central B-chain residue (B16Ile). These three determinant residues together with the C-terminal carboxylate moiety probably constitute a central receptor-binding patch that forms critical hydrophobic and electrostatic interactions with RXFP4 during INSL5 binding. Some other exposed residues, including B10Glu, B12Ile, B13Arg, B17Tyr, B21Ser, and B22Ser, made minor contributions to INSL5 function. These auxiliary residues are scattered around the edge of the central receptor-binding patch, and thus form a peripheral receptor-binding patch on the surface of INSL5. Our present work provides new insights into the interaction mechanism of INSL5 with its receptor RXFP4.
      Graphical abstract image

      PubDate: 2017-03-08T23:12:59Z
      DOI: 10.1016/
      Issue No: Vol. 619 (2017)
  • Interaction of glyceraldehyde-3-phosphate dehydrogenase and heme: The
           relevance of its biological function
    • Authors: Yi Huang; Pengfei Zhang; Zhen Yang; Peipei Wang; Hailing Li; Zhonghong Gao
      Pages: 54 - 61
      Abstract: Publication date: 1 April 2017
      Source:Archives of Biochemistry and Biophysics, Volume 619
      Author(s): Yi Huang, Pengfei Zhang, Zhen Yang, Peipei Wang, Hailing Li, Zhonghong Gao
      GAPDH was speculated to function as a transient trap to reduce the potential toxicity of free heme by a specific and reversible binding with heme. Up to now, there has been lack of studies focused on this effect. In this paper, the efficiency of GAPDH-heme complex on catalyzing protein carbonylation and nitration, the cross-linking of heme to protein formation, and cytotoxicity of GAPDH-heme were studied. It was found that the binding of GAPDH could inhibit H2O2-mediated degradation of heme. Peroxidase activity of GAPDH-heme complex was higher than that of free heme, but significantly lower than that of HSA-heme. Catalytic activity of heme corresponded complex toward tyrosine oxidation/nitration was decreased in the order of HSA-heme, heme and GAPDH-heme. GAPDH also inhibited heme-H2O2-NO2 - induced protein carbonylation. No covalent bond was formed between heme and GAPDH after treated with H2O2. GAPDH was more effective than HSA on protecting cells against heme-NO2 --H2O2 induced cytotoxicity. These results indicate that binding of GAPDH inhibits the activity of heme in catalyzing tyrosine nitration and protects the coexistent protein against oxidative damage, and the mechanism is different from that of HSA. This study may help clarifying the protective role of GAPDH acting as a chaperone in heme transfer to downstream areas.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
      Issue No: Vol. 619 (2017)
  • Corrigendum to “Conformational status of cytochrome c upon
           N-homocysteinylation: Implications to cytochrome c release”
           [Arch. Biochem. Biophys. 614 (2017) 23–27]
    • Authors: Gurumayum Suraj Sharma; Laishram Rajendrakumar Singh
      First page: 44
      Abstract: Publication date: 15 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 618
      Author(s): Gurumayum Suraj Sharma, Laishram Rajendrakumar Singh

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
      Issue No: Vol. 618 (2017)
  • A scalable lysyl hydroxylase 2 expression system and luciferase-based
           enzymatic activity assay
    • Authors: Hou-Fu Guo; Eun Jeong Cho; Ashwini K. Devkota; Yulong Chen; William Russell; George N. Phillips; Mitsuo Yamauchi; Kevin N. Dalby; Jonathan M. Kurie
      Pages: 45 - 51
      Abstract: Publication date: Available online 20 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Hou-Fu Guo, Eun Jeong Cho, Ashwini K. Devkota, Yulong Chen, William Russell, George N. Phillips, Mitsuo Yamauchi, Kevin N. Dalby, Jonathan M. Kurie
      Hydroxylysine aldehyde-derived collagen cross-links (HLCCs) accumulate in fibrotic tissues and certain types of cancer and are thought to drive the progression of these diseases. HLCC formation is initiated by lysyl hydroxylase 2 (LH2), an Fe(II) and α-ketoglutarate (αKG)-dependent oxygenase that hydroxylates telopeptidyl lysine residues on collagen. Development of LH2 antagonists for the treatment of these diseases will require a reliable source of recombinant LH2 protein and a non-radioactive LH2 enzymatic activity assay that is amenable to high throughput screens of small molecule libraries. However, LH2 protein generated previously using E coli– or insect-based expression systems was either insoluble or enzymatically unstable, and LH2 enzymatic activity assays have measured radioactive CO2 released from 14C-labeled αKG during its conversion to succinate. To address these deficiencies, we have developed a scalable process to purify human LH2 protein from Chinese hamster ovary cell-derived conditioned media samples and a luciferase-based assay that quantifies LH2-dependent conversion of αKG to succinate. These methodologies may be applicable to other Fe(II) and αKG-dependent oxygenase systems.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 618 (2017)
  • Signaling by sulfur-containing molecules. Quantitative aspects
    • Authors: Willem H. Koppenol; Patricia L. Bounds
      Pages: 3 - 8
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Willem H. Koppenol, Patricia L. Bounds
      There is currently interest in sulfur-containing molecules that may or may not play a role in signaling. We have collected relevant thermodynamic data, namely standard Gibbs energies of formation and electrode potentials at pH 7, and used these to construct a Frost diagram. Thermodynamic data not available in the literature could be estimated with reasonable confidence. At pH 7, the electrode potential of the RSS/RSS− couple is +0.68 V, 0.28 V less than that of the RS, H+/RSH couple. S2 − is unstable with respect to HSS− and S2. Generally, polysulfur compounds, with the exception of RSSR, are thermodynamically unstable with respect to disproportionation and ultimately lead to formation of kinetically inert S8(s). About thermoneutral is the formation of RSS− from RSSR and HS−, but formation of HNO from HS− and SNO−, and from HS− and RSNO, is unfavorable. The formation of SSNO− in vivo is kinetically unlikely.
      Graphical abstract image

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Biological chemistry of hydrogen sulfide and persulfides
    • Authors: Ernesto Cuevasanta; Matías N. Möller; Beatriz Alvarez
      Pages: 9 - 25
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Ernesto Cuevasanta, Matías N. Möller, Beatriz Alvarez
      Hydrogen sulfide (H2S) has been traditionally considered to be a toxic molecule for mammals. However, it can be formed endogenously and exert physiological effects with potential health benefits. H2S can partition two-fold in biological membranes and traverse them rapidly, diffusing between compartments. H2S reactivity has similarities to that of thiols, although it is less nucleophilic than thiols and it can form different products. H2S can react with oxidants derived from the partial reduction of oxygen, but direct scavenging is unlikely to explain H2S protective actions. Important effects are exerted on mitochondria including the stimulation or the inhibition of the electron transport chain. Possible mechanisms for unleashing biological consequences are the reactions with metal centers and with thiol oxidation products. The reactions of H2S with disulfides (RSSR) and sulfenic acids (RSOH) lead to the formation of persulfides (RSSH). Persulfides have enhanced nucleophilicity with respect to the corresponding thiol, consistent with the alpha effect. Besides, the inner and outer sulfurs can both act as electrophiles. In this review, we describe the reactions of H2S with oxidized thiol products and the properties of the persulfides formed in the context of the chemical biology of H2S.
      Graphical abstract image

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Protein cysteine oxidation in redox signaling: Caveats on sulfenic acid
           detection and quantification
    • Authors: Henry Jay Forman; Michael J. Davies; Anna C. Krämer; Giovanni Miotto; Mattia Zaccarin; Hongqiao Zhang; Fulvio Ursini
      Pages: 26 - 37
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Henry Jay Forman, Michael J. Davies, Anna C. Krämer, Giovanni Miotto, Mattia Zaccarin, Hongqiao Zhang, Fulvio Ursini
      Oxidation of critical signaling protein cysteines regulated by H2O2 has been considered to involve sulfenic acid (RSOH) formation. RSOH may subsequently form either a sulfenyl amide (RSNHR′) with a neighboring amide, or a mixed disulfide (RSSR′) with another protein cysteine or glutathione. Previous studies have claimed that RSOH can be detected as an adduct (e.g., with 5,5-dimethylcyclohexane-1,3-dione; dimedone). Here, kinetic data are discussed which indicate that few proteins can form RSOH under physiological signaling conditions. We also present experimental evidence that indicates that (1) dimedone reacts rapidly with sulfenyl amides, and more rapidly than with sulfenic acids, and (2) that disulfides can react reversibly with amides to form sulfenyl amides. As some proteins are more stable as the sulfenyl amide than as a glutathionylated species, the former may account for some of the species previously identified as the “sulfenome” - the cellular complement of reversibly-oxidized thiol proteins generated via sulfenic acids.
      Graphical abstract image

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Recent developments in detection of superoxide radical anion and hydrogen
           peroxide: Opportunities, challenges, and implications in redox signaling
    • Authors: Balaraman Kalyanaraman; Micael Hardy; Radoslaw Podsiadly; Gang Cheng; Jacek Zielonka
      Pages: 38 - 47
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Balaraman Kalyanaraman, Micael Hardy, Radoslaw Podsiadly, Gang Cheng, Jacek Zielonka
      In this review, some of the recent developments in probes and assay techniques specific for superoxide (O2 –) and hydrogen peroxide (H2O2) are discussed. Over the last decade, significant progress has been made in O2 – and H2O2 detection due to syntheses of new redox probes, better understanding of their chemistry, and development of specific and sensitive assays. For superoxide detection, hydroethidine (HE) is the most suitable probe, as the product, 2-hydroxyethidium, is specific for O2 –. In addition, HE-derived dimeric products are specific for one-electron oxidants. As red-fluorescent ethidium is always formed from HE intracellularly, chromatographic techniques are required for detecting 2-hydroxyethidium. HE analogs, Mito-SOX and hydropropidine, exhibit the same reaction chemistry with O2 – and one-electron oxidants. Thus, mitochondrial superoxide can be unequivocally detected using HPLC-based methods and not by fluorescence microscopy. Aromatic boronate-based probes react quantitatively with H2O2, forming a phenolic product. However, peroxynitrite and hypochlorite react more rapidly with boronates, forming the same product. Using ROS-specific probes and HPLC assays, it is possible to screen chemical libraries to discover specific inhibitors of NADPH oxidases. We hope that rigorous detection of O2 – and H2O2 in different cellular compartments will improve our understanding of their role in redox signaling.
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      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Selenium and redox signaling
    • Authors: Regina Brigelius-Flohé; Leopold Flohé
      Pages: 48 - 59
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Regina Brigelius-Flohé, Leopold Flohé
      Selenium compounds that contain selenol functions or can be metabolized to selenols are toxic via superoxide and H2O2 generation, when ingested at dosages beyond requirement. At supra-nutritional dosages various forms of programmed cell death are observed. At physiological intakes, selenium exerts its function as constituent of selenoproteins, which overwhelmingly are oxidoreductases. Out of those, the glutathione peroxidases counteract hydroperoxide-stimulated signaling cascades comprising inflammation triggered by cytokines or lipid mediators, insulin signaling and different forms of programmed cell death. Similar events are exerted by peroxiredoxins, which functionally depend on the selenoproteins of the thioredoxin reductase family. The thiol peroxidases of both families can, however, also act as sensors for hydroperoxides, thereby initiating signaling cascades. Although the interaction of selenoproteins with signaling events has been established by genetic techniques, the in vivo relevance of these findings is still hard to delineate for several reasons: The biosynthesis of individual selenoproteins responds differently to variations of selenium intakes; selenium is preferentially delivered to privileged tissues via inter-organ trafficking and receptor-mediated uptake, and only half of the selenoproteins known by sequence have been functionally characterized. The fragmentary insights do not allow any uncritical use of selenium for optimizing human health.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • The role of peroxiredoxin 1 in redox sensing and transducing
    • Authors: Elizabeth C. Ledgerwood; James W.A. Marshall; Johannes F. Weijman
      Pages: 60 - 67
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Elizabeth C. Ledgerwood, James W.A. Marshall, Johannes F. Weijman
      Peroxiredoxin 1 is a member of the ubiquitous peroxiredoxin family of thiol peroxidases that catalyse the reduction of peroxides. In recent years eukaryotic peroxiredoxins have emerged as a critical component of cellular redox signalling, particularly in response to alterations in production of hydrogen peroxide. Peroxiredoxins are exquisitely sensitive to oxidation by hydrogen peroxide making them key peroxide sensing enzymes within cells. Evidence gathered over the last decade suggests that in addition to sensing the redox signal, peroxiredoxins have a major role in transducing this signal to downstream signalling proteins, ultimately contributing to regulation of diverse cellular processes including proliferation, differentiation and apoptosis. In this review we present the three current models for the sensing and signal transducing roles of peroxiredoxins, with a specific focus on mammalian peroxiredoxin 1. The evidence for each mechanism is discussed and areas for future work are identified.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Keap1, the cysteine-based mammalian intracellular sensor for electrophiles
           and oxidants
    • Authors: Albena T. Dinkova-Kostova; Rumen V. Kostov; Peter Canning
      Pages: 84 - 93
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Albena T. Dinkova-Kostova, Rumen V. Kostov, Peter Canning
      The Kelch-like ECH associated protein 1 (Keap1) is a component of a Cullin3-based Cullin-RING E3 ubiquitin ligase (CRL) multisubunit protein complex. Within the CRL, homodimeric Keap1 functions as the Cullin3 adaptor, and importantly, it is also the critical component of the E3 ligase that performs the substrate recognition. The best-characterized substrate of Keap1 is transcription factor NF-E2 p45-related factor 2 (Nrf2), which orchestrates an elaborate transcriptional program in response to environmental challenges caused by oxidants, electrophiles and pro-inflammatory agents, allowing adaptation and survival under stress conditions. Keap1 is equipped with reactive cysteine residues that act as sensors for endogenously produced and exogenously encountered small molecules (termed inducers), which have a characteristic chemical signature, reactivity with sulfhydryl groups. Inducers modify the cysteine sensors of Keap1 and impair its ability to target Nrf2 for ubiquitination and degradation. Consequently, Nrf2 accumulates, enters the nucleus and drives the transcription of its target genes, which encode a large network of cytoprotective proteins. Here we summarize the early studies leading to the prediction of the existence of Keap1, followed by the discovery of Keap1 as the main negative regulator of Nrf2. We then describe the available structural information on Keap1, its assembly with Cullin3, and its interaction with Nrf2. We also discuss the multiple cysteine sensors of Keap1 that allow for detection of a wide range of endogenous and environmental inducers, and provide fine-tuning and tight control of the Keap1/Nrf2 stress-sensing response.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Keap1 as the redox sensor of the antioxidant response
    • Authors: Virve Sihvola; Anna-Liisa Levonen
      Pages: 94 - 100
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Virve Sihvola, Anna-Liisa Levonen
      Reactive oxygen species (ROS) and products of their reactions with cellular macromolecules such as unsaturated fatty acids have been implicated to be important regulators of signalling processes via oxidation or alkylation of redox active thiol residues in target proteins. One of key redox-sensitive signalling proteins mediating the response to oxidant stress is Keap1 (Kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1), which is a negative regulator of transcription factor Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and the central hub for sensing endogenous and environmental oxidative and electrophilic stress. In this review, we provide an overview of the mechanisms by which Keap1 orchestrates the antioxidant response and how the system can be targeted for therapy.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Thioredoxin and redox signaling: Roles of the thioredoxin system in
           control of cell fate
    • Authors: Atsushi Matsuzawa
      Pages: 101 - 105
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Atsushi Matsuzawa
      Reactive oxygen species (ROS) are not only cytotoxic products from external and internal environment, but also important mediators of redox signaling. Therefore, thioredoxin (Trx) as an antioxidant maintains the balance of the thiol-related redox status, and also plays pivotal roles in the regulation of redox signaling. Trx senses and responds to environmental oxidative stress and ROS generated by cellular respiration, metabolism, and immune response, and then modulates the redox status, function, and activity of its target signaling proteins. Dysregulation of such the Trx system affects various cellular functions and cell fate such as survival and cell death, leading to human diseases including cancer and inflammation. This review focuses on Trx and its target proteins involved in redox signaling, which are critical for the control of cell fate such as cell survival and apoptosis, and addresses how Trx regulates those effector proteins and redox signaling.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Protein disulfide isomerases: Redox connections in and out of the
           endoplasmic reticulum
    • Authors: Ana Iochabel Soares Moretti; Francisco Rafael Martins Laurindo
      Pages: 106 - 119
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Ana Iochabel Soares Moretti, Francisco Rafael Martins Laurindo
      Protein disulfide isomerases are thiol oxidoreductase chaperones from thioredoxin superfamily. As redox folding catalysts from the endoplasmic reticulum (ER), their roles in ER-related redox homeostasis and signaling are well-studied. PDIA1 exerts thiol oxidation/reduction and isomerization, plus chaperone effects. Also, substantial evidence indicates that PDIs regulate thiol-disulfide switches in other cell locations such as cell surface and possibly cytosol. Subcellular PDI translocation routes remain unclear and seem Golgi-independent. The list of signaling and structural proteins reportedly regulated by PDIs keeps growing, via thiol switches involving oxidation, reduction and isomerization, S-(de)nytrosylation, (de)glutathyonylation and protein oligomerization. PDIA1 is required for agonist-triggered Nox NADPH oxidase activation and cell migration in vascular cells and macrophages, while PDIA1-dependent cytoskeletal regulation appears a converging pathway. Extracellularly, PDIs crucially regulate thiol redox signaling of thrombosis/platelet activation, e.g., integrins, and PDIA1 supports expansive caliber remodeling during injury repair via matrix/cytoskeletal organization. Some proteins display regulatory PDI-like motifs. PDI effects are orchestrated by expression levels or post-translational modifications. PDI is redox-sensitive, although probably not a mass-effect redox sensor due to kinetic constraints. Rather, the “all-in-one” organization of its peculiar redox/chaperone properties likely provide PDIs with precision and versatility in redox signaling, making them promising therapeutic targets.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Redox status in a model of cancer stem cells
    • Authors: Mattia Zaccarin; Valentina Bosello-Travain; Maria Luisa Di Paolo; Marco Falda; Matilde Maiorino; Giovanni Miotto; Stefano Piccolo; Antonella Roveri; Fulvio Ursini; Rina Venerando; Stefano Toppo
      Pages: 120 - 128
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Mattia Zaccarin, Valentina Bosello-Travain, Maria Luisa Di Paolo, Marco Falda, Matilde Maiorino, Giovanni Miotto, Stefano Piccolo, Antonella Roveri, Fulvio Ursini, Rina Venerando, Stefano Toppo
      Reversible oxidation of Cys residues is a crucial element of redox homeostasis and signaling. According to a popular concept in oxidative stress signaling, the oxidation of targets of signals can only take place following an overwhelming of the cellular antioxidant capacity. This concept, however, ignores the activation of feedback mechanisms possibly leading to a paradoxical effect. In a model of cancer stem cells (CSC), stably overexpressing the TAZ oncogene, we observed that the increased formation of oxidants is associated with a globally more reduced state of proteins. Redox proteomics revealed that several proteins, capable of undergoing reversible redox transitions, are indeed more reduced while just few are more oxidized. Among the proteins more oxidized, G6PDH emerges as both more expressed and activated by oxidation. This accounts for the observed more reduced state of the NADPH/NADP+ couple. The dynamic redox flux generating this apparently paradoxical effect is rationalized in a computational system biology model highlighting the crucial role of G6PDH activity on the rate of redox transitions eventually leading to the reduction of reversible redox switches.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • The chemical biology of HNO signaling
    • Authors: Christopher L. Bianco; John P. Toscano; Michael D. Bartberger; Jon M. Fukuto
      Pages: 129 - 136
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Christopher L. Bianco, John P. Toscano, Michael D. Bartberger, Jon M. Fukuto
      Nitroxyl (HNO) is a simple molecule with significant potential as a pharmacological agent. For example, its use in the possible treatment of heart failure has received recent attention due to its unique therapeutic properties. Recent progress has been made on the elucidation of the mechanisms associated with its biological signaling. Importantly, the biochemical mechanisms described for HNO bioactivity are consistent with its unique and novel chemical properties/reactivity. To date, much of the biology of HNO can be associated with interactions and modification of important regulatory thiol proteins. Herein will be provided a description of HNO chemistry and how this chemistry translates to some of its reported biological effects.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • How are nitrosothiols formed de novo in vivo?
    • Authors: Jack R. Lancaster
      Pages: 137 - 144
      Abstract: Publication date: 1 March 2017
      Source:Archives of Biochemistry and Biophysics, Volume 617
      Author(s): Jack R. Lancaster
      The biological mechanisms of de novo formation of cellular nitrosothiols (as opposed to transnitrosation) are reviewed. The approach is to introduce chemical foundations for each mechanism, followed by evidence in biological systems. The general categories include mechanisms involving nitrous acid, NO autoxidation and oxidant stress, redox active and inactive metal ions, and sulfide/persulfide. Important conclusions/speculations are that de novo cellular thiol nitrosation (1) is an oxidative process, and so should be considered within the family of other thiol oxidative modifications, (2) may not involve a single dominant process but depends on the specific conditions, (3) does not involve O2 under at least some conditions, and (4) may serve to provide a “substrate pool” of protein cysteine nitrosothiol which could, through subsequent enzymatic transnitrosation/denitrosation, be “rearranged” to accomplish the specificity and regulatory control required for effective post-translational signaling.

      PubDate: 2017-02-23T16:50:05Z
      DOI: 10.1016/
      Issue No: Vol. 617 (2017)
  • Stimulatory and inhibitory effects of PKC isozymes are mediated by
           serine/threonine PKC sites of the Cav2.3α1 subunits
    • Authors: Ganesan L. Kamatchi; Senthilkumar Rajagopal; Brittney K. Burton
      First page: 399a
      Abstract: Publication date: 1 May 2017
      Source:Archives of Biochemistry and Biophysics, Volume 621
      Author(s): Senthilkumar Rajagopal, Brittney K. Burton, Blanche L. Fields, India O. El, Ganesan L. Kamatchi
      Protein kinase C (PKC) isozymes modulate voltage-gated calcium (Cav) currents through Cav2.2 and Cav2.3 channels by targeting serine/threonine (Ser/Thr) phosphorylation sites of Cavα1 subunits. Stimulatory (Thr-422, Ser-2108 and Ser-2132) and inhibitory (Ser-425) sites were identified in the Cav2.2α1 subunits to PKCs βII and ε. In the current study, we investigated if the homologous sites of Cav2.3α1 subunits (stimulatory: Thr-365, Ser-1995 and Ser-2011; inhibitory: Ser-369) behaved in similar manner. Several Ala and Asp mutants were constructed in Cav2.3α1 subunits in such a way that the Ser/Thr sites can be examined in isolation. These mutants or WT Cav2.3α1 along with auxiliary β1b and α2/δ subunits were expressed in Xenopus oocytes and the effects of PKCs βII and ε studied on the barium current (I Ba). Among these sites, stimulatory Thr-365 and Ser-1995 and inhibitory Ser-369 behaved similar to their homologs in Cav2.2α1 subunits. Furthermore PKCs produced neither stimulation nor inhibition when stimulatory Thr-365 or Ser-1995 and inhibitory Ser-369 were present together. However, the PKCs potentiated the I Ba when two stimulatory sites, Thr-365 and Ser-1995 were present together, thus overcoming the inhibitory effect of Ser-369. Taken together net PKC effect may be the difference between the responses of the stimulatory and inhibitory sites.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/j.bpj.2016.11.2166
      Issue No: Vol. 112, No. 3 (2017)
  • TRIB3 downregulation enhances doxorubicin-induced cytotoxicity in gastric
           cancer cells
    • Authors: I-Jung Wu; Rong-Jaan Lin; Hsin-Chiao Wang; Tein-Ming Yuan; Show-Mei Chuang
      Abstract: Publication date: Available online 23 April 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): I-Jung Wu, Rong-Jaan Lin, Hsin-Chiao Wang, Tein-Ming Yuan, Show-Mei Chuang
      TRIB3, which is a pseudokinase known to regulate multiple pro-survival pathways, appears to be a potential therapeutic target for the treatment of human tumors. However, its precise role in cancer is controversial, as TRIB3 protein levels have been associated with both good and poor prognosis in cancer patients. Here, we investigated the significance of TRIB3 expression in the survival of gastric cancer cells exposed to anticancer drugs. We found that the tested anticancer drug, doxorubicin, induced cytotoxicity by decreasing TRIB3 transcription, which was followed by apoptotic cell death. Moreover, TRIB3 siRNA knockdown appeared to enhance doxorubicin-induced apoptosis in gastric cancer cells, concurrently with altering the expression of downstream apoptotic factors. Conversely, overexpression of TRIB3 significantly protected cells against doxorubicin-induced apoptosis. Our results indicate that downregulation of TRIB3 appears to promote cell death and enhance doxorubicin-induced apoptosis, supporting the anti-apoptotic role of TRIB3. The inductions of three classes of MAPKs failed to affect doxorubicin-mediated TRIB3 downregulation, while TRIB3 overexpression did not affect doxorubicin-induced MAPK activation. In sum, our findings indicate that TRIB3 plays an anti-apoptotic role in doxorubicin-treated gastric cancer cell lines, perhaps indicating that the status of TRIB3 expression in response to anticancer drugs, such as doxorubicin, irinotecan or oxaliplatin, may reflect the efficiency for cancer therapy.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
  • Abnormal lipid/lipoprotein metabolism and high plasma testosterone levels
           in male but not female aromatase-knockout mice
    • Authors: Akiko Amano; Yoshitaka Kondo; Yoshihiro Noda; Mitsuhiro Ohta; Noriaki Kawanishi; Shuichi Machida; Kazuteru Mitsuhashi; Takafumi Senmaru; Michiaki Fukui; Osamu Takaoka; Taisuke Mori; Jo Kitawaki; Masafumi Ono; Toshiji Saibara; Hiroshi Obayashi; Akihito Ishigami
      Abstract: Publication date: Available online 22 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Akiko Amano, Yoshitaka Kondo, Yoshihiro Noda, Mitsuhiro Ohta, Noriaki Kawanishi, Shuichi Machida, Kazuteru Mitsuhashi, Takafumi Senmaru, Michiaki Fukui, Osamu Takaoka, Taisuke Mori, Jo Kitawaki, Masafumi Ono, Toshiji Saibara, Hiroshi Obayashi, Akihito Ishigami
      Sex steroid hormones, such as estrogen and testosterone, are believed to play important roles in lipid metabolism. To elucidate the effects of estrogen depletion on lipid metabolism in male and female mice, we used aromatase-knockout (ArKO) mice, in which Cyp19 gene disruption prevented estrogen synthesis in vivo. These mice were divided into the following 4 groups: male and female ArKO mice and male and female wild-type (WT) mice. These mice were fed a normal-fat diet (13.6% fat) ad libitum. At 159 days after birth, the mice were tested for liver and plasma lipid content and hepatic hormone receptor- and lipid/lipoprotein metabolism-related gene expression. Interestingly, we found that hepatic steatosis was accompanied by markedly elevated plasma testosterone levels in male ArKO mice but not in female ArKO mice. Plasma lipoprotein profiles exhibited concurrent decreases in LDL- and small dense LDL-triglyceride (TG) levels in male ArKO mice. Moreover, male mice, but not female mice, exhibited marked elevations in androgen receptor (AR), sterol regulatory element-binding protein 1 (SREBP1), and CD36 expression. These results strongly suggest that Cyp19 gene disruption, which induces a sexually dimorphic response and high plasma testosterone levels in male mice, also induces hepatic steatosis.

      PubDate: 2017-04-25T03:08:37Z
      DOI: 10.1016/
  • Hydroxylation of 4-hydroxyphenylethylamine derivatives by R263 variants of
           the oxygenase component of p-hydroxyphenylacetate-3-hydroxylase
    • Authors: Pirom Chenprakhon; Taweesak Dhammaraj; Rattikan Chantiwas; Pimchai Chaiyen
      Abstract: Publication date: Available online 12 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Pirom Chenprakhon, Taweesak Dhammaraj, Rattikan Chantiwas, Pimchai Chaiyen
      p-hydroxyphenylacetate 3-hydroxylase from Acinetobacter baumannii catalyzes the hydroxylation of p-hydroxyphenylacetate (HPA) to yield 3,4-dihydroxyphenylacetate (DHPA). In this study, we investigated whether variants of the oxygenase component (C2) could catalyze hydroxylation of 4-hydroxyphenylethylamines to synthesize catecholamine derivatives. Single turnover product analysis showed that the R263D variant can catalyze hydroxylation of tyramine to form dopamine with the highest yield (57%). The enzyme was also found to have dual substrate charge specificity because it can also maintain reasonable hydroxylation efficiency of HPA (86%). This property is different from the R263E variant, which can hydroxylate HPA (73%) but not tyramine. The R263A variant can hydroxylate HPA (72%) and tyramine to a small extent (7%). Stopped-flow experiments indicated that tyramine and HPA prefer binding to R263D after C4a-hydroperoxy-FMN formation, while tyramine cannot bind to the wild-type or R263E enzymes. Data also indicate that the hydroxylation rate constant is the rate-limiting step. The R263D variant was used as a starting enzyme for further mutation to obtain other variants for the synthesis of additional catecholamine drugs. The R263D/Y398D double mutant enzyme showed interesting results in that it was able to catalyze the hydroxylation of octopamine to form norepinephrine. However, the enzyme still lacked stereo-selectivity in its reaction.
      Graphical abstract image

      PubDate: 2017-03-12T23:13:42Z
      DOI: 10.1016/
  • Overcoming electrostatic repulsions during amyloid assembly: Effect of pH
           and interaction with divalent metals using model peptides
    • Authors: Octavio Monasterio; Esteban Nova; Rodrigo Diaz-Espinoza
      Abstract: Publication date: Available online 10 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Octavio Monasterio, Esteban Nova, Rodrigo Diaz-Espinoza
      Amyloids are polypeptide aggregates involved in many pathologies including Alzheimer's disease. Amyloid assembly is a complex process affected by different interactions including hydrogen bonding, van der Waals forces and electrostatic interactions. The highly regular amyloid structure allows for an arrangement of residues that forces side chains to be closely positioned, giving rise to potentially unfavorable interactions such as electrostatic repulsions. In these cases, amyloid assembly will depend on a balance between stabilizing versus unfavorable interactions. In this study, we rationally designed several amyloid-prone model peptides that had two acidic groups and tested their assembly into amyloids under different conditions. We found that at low pH (pH 4.0), most peptides spontaneously formed amyloids whereas no or little aggregation was observed at higher pHs (pH 8.0). When divalent metals with affinity for carboxylate groups were added at millimolar concentrations, most peptides exhibited a metal-dependent switch to the amyloid state at pH 8.0. Our results show that electrostatic repulsion between amyloid-prone sequences can be overcome in conditions that affect protonation of residue side chains. Moreover, the presence of divalent metals can contribute to electrostatic shielding through specific coordination with acidic groups and thus promote amyloid assembly at near-physiological conditions.
      Graphical abstract image

      PubDate: 2017-03-12T23:13:42Z
      DOI: 10.1016/
  • Minimized natural versions of fungal ribotoxins show improved active site
    • Authors: Moisés Maestro-López; Miriam Olombrada; Lucía García-Ortega; Daniel Serrano-González; Javier Lacadena; Mercedes Oñaderra; José G. Gavilanes; Álvaro Martínez-del-Pozo
      Abstract: Publication date: Available online 7 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Moisés Maestro-López, Miriam Olombrada, Lucía García-Ortega, Daniel Serrano-González, Javier Lacadena, Mercedes Oñaderra, José G. Gavilanes, Álvaro Martínez-del-Pozo
      Fungal ribotoxins are highly specific extracellular RNases which cleave a single phosphodiester bond at the ribosomal sarcin-ricin loop, inhibiting protein biosynthesis by interfering with elongation factors. Most ribotoxins show high degree of conservation, with similar sizes and amino acid sequence identities above 85%. Only two exceptions are known: Hirsutellin A and anisoplin, produced by the entomopathogenic fungi Hirsutella thompsonii and Metarhizium anisopliae, respectively. Both proteins are similar but smaller than the other known ribotoxins (130 vs 150 amino acids), displaying only about 25% sequence identity with them. They can be considered minimized natural versions of their larger counterparts, best represented by α-sarcin. The conserved α-sarcin active site residue Tyr48 has been replaced by the geometrically equivalent Asp, present in the minimized ribotoxins, to produce and characterize the corresponding mutant. As a control, the inverse anisoplin mutant (D43Y) has been also studied. The results show how the smaller versions of ribotoxins represent an optimum compromise among conformational freedom, stability, specificity, and active-site plasticity which allow these toxic proteins to accommodate the characteristic abilities of ribotoxins into a shorter amino acid sequence and more stable structure of intermediate size between that of other nontoxic fungal RNases and previously known larger ribotoxins.

      PubDate: 2017-03-08T23:12:59Z
      DOI: 10.1016/
  • NMR-based automated protein structure determination
    • Authors: Julia M. Würz; Sina Kazemi; Elena Schmidt; Anurag Bagaria; Peter Güntert
      Abstract: Publication date: Available online 2 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Julia M. Würz, Sina Kazemi, Elena Schmidt, Anurag Bagaria, Peter Güntert
      NMR spectra analysis for protein structure determination can now in many cases be performed by automated computational methods. This overview of the computational methods for NMR protein structure analysis presents recent automated methods for signal identification in multidimensional NMR spectra, sequence-specific resonance assignment, collection of conformational restraints, and structure calculation, as implemented in the CYANA software package. These algorithms are sufficiently reliable and integrated into one software package to enable the fully automated structure determination of proteins starting from NMR spectra without manual interventions or corrections at intermediate steps, with an accuracy of 1–2 Å backbone RMSD in comparison with manually solved reference structures.

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
  • NMR-based Stable Isotope Resolved Metabolomics in systems biochemistry
    • Authors: Andrew N. Lane; Teresa W-M. Fan
      Abstract: Publication date: Available online 2 March 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Andrew N. Lane, Teresa W-M. Fan
      Metabolism is the basic activity of live cells, and monitoring the metabolic state provides a dynamic picture of the cells or tissues, and how they respond to external changes, for in disease or treatment with drugs. NMR is an extremely versatile analytical tool that can be applied to a wide range of biochemical problems. Despite its modest sensitivity its versatility make it an ideal tool for analyzing biochemical dynamics both in vitro and in vivo, especially when coupled with its isotope editing capabilities, from which isotope distributions can be readily determined. These are critical for any analyses of flux in live organisms. This review focuses on the utility of NMR spectroscopy in metabolomics, with an emphasis on NMR applications in stable isotope-enriched tracer research for elucidating biochemical pathways and networks with examples from nucleotide biochemistry. The knowledge gained from this area of research provides a ready link to genomic, epigenomic, transcriptomic, and proteomic information to achieve systems biochemical understanding of living cells and organisms.

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
  • Red/ox states of human protein disulfide isomerase regulates binding
           affinity of 17-Beta-Estradiol
    • Authors: Razieh Karamzadeh; Mohammad Hossein Karimi-Jafari; Ali Akbar Saboury; Ghasem Hosseini-Salekdeh; Ali Akbar Moosavi-Movahedi
      Abstract: Publication date: Available online 28 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Razieh Karamzadeh, Mohammad Hossein Karimi-Jafari, Ali Akbar Saboury, Ghasem Hosseini-Salekdeh, Ali Akbar Moosavi-Movahedi
      Human protein disulfide isomerase (hPDI) is a key redox-regulated thiol-containing protein operating as both oxidoreductase and molecular chaperone in the endoplasmic reticulum of cells. hPDI thiol-disulfide interchange reactions lead to the adoption of two distinct red/ox conformations with different substrate preferences. hPDI also displays high binding capacity for some exogenous steroid hormones including 17-Beta-Estradiol (E2) and thus contributes to the regulation of their intracellular concentration, storage and actions. The primary focus of this study is to investigate the impact of E2 binding on functional activity of recombinant hPDI. Then, we examine the effect of E2 binding on structural alteration of hPDI red/ox conformations and its influence on affinity and position of interaction using experimental and computational analysis. Our results revealed that interaction of one E2 per each hPDI molecule leads to the inhibition of hPDI reductase activity and conformational changes in both oxidation states. Mutually, E2-binding position are also redox-regulated with higher affinity in oxidized hPDI compare to the reduced form. The importance of histidine-256 protonation states in distinct binding preferences of E2 were also demonstrated in hPDI red/ox conformations. These findings might pave the way for better understanding of the mechanisms behind the redox-dependent hormone-binding activity of hPDI.

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
  • Targeting thioredoxin reductase by plumbagin contributes to inducing
           apoptosis of HL-60 cells
    • Authors: Junmin Zhang; Shoujiao Peng; Xinming Li; Ruijuan Liu; Xiao Han; Jianguo Fang
      Abstract: Publication date: Available online 27 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Junmin Zhang, Shoujiao Peng, Xinming Li, Ruijuan Liu, Xiao Han, Jianguo Fang
      Plumbagin (PLB), a natural naphthoquinone from the traditional folk medicines Plumbago zeylanica, Dionaea muscipula, or Nepenthes gracilis, has been documented possessing a wide variety of pharmacological activities. Although PLB demonstrates anticancer activity in multiple types of malignant cells, the cellular targets of PLB have not been well defined and remained only partially understood. We reported here that PLB selectively inhibits TrxR and elicits reactive oxygen species in human promyelocytic leukemia HL-60 cells, which leads to elevation of GSSG/GSH ratio and decrease of cellular thiol pool. As a consequence, PLB disturbs the cellular redox homeostasis, induces oxidative stress-mediated apoptosis and eventually selectively kills HL-60 cells. Inhibition of TrxR by PLB thus discloses an unprecedented mechanism underlying the anticancer efficacy of PLB, and sheds light in considering the usage of PLB as a promising cancer therapeutic agent.
      Graphical abstract image

      PubDate: 2017-03-02T23:11:53Z
      DOI: 10.1016/
  • Identification and characterization of a novel starch branching enzyme
           from the picoalgae Ostreococcus tauri
    • Authors: Nicolas Hedin; Julieta Barchiesi Diego Gomez-Casati Alberto Iglesias Miguel Ballicora
      Abstract: Publication date: Available online 21 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Nicolas Hedin, Julieta Barchiesi, Diego F. Gomez-Casati, Alberto A. Iglesias, Miguel A. Ballicora, María V. Busi
      Starch branching enzyme is a highly conserved protein from plants to algae. This enzyme participates in starch granule assembly by the addition of α-1,6-glucan branches to the α-1,4-polyglucans. This modification determines the structure of amylopectin thus arranging the final composition of the starch granule. Herein, we describe the function of the Ot01g03030 gene from the picoalgae Ostreococcus tauri. Although in silico analysis suggested that this gene codes for a starch debranching enzyme, our biochemical studies support that this gene encodes a branching enzyme (BE). The resulting 1058 amino acids protein has two in tandem carbohydrate binding domains (CBMs, from the CBM41 and CBM48 families) at the N-terminal (residues 64–403) followed by the C-terminal catalytic domain (residues 426–1058). Analysis of the BE truncated isoforms show that the CBMs bind differentially to whole starch, amylose or amylopectin. Furthermore, both CBMs seem to be essential for BE activity, as no catalytic activity was detected in the truncated enzyme comprising only by the catalytic domain. Our results suggest that the Ot01g03030 gene codifies for a functional BE containing two CBMs from CBM41 and CBM48 families which are critical for enzyme function and regulation.

      PubDate: 2017-02-23T16:50:05Z
  • Characterization of Acyl-CoA synthetase isoforms in pancreatic beta cells:
           Gene silencing shows participation of ACSL3 and ACSL4 in insulin secretion
    • Authors: Israr-ul H. Ansari; Melissa J. Longacre; Scott W. Stoker; Mindy A. Kendrick; Lucas M. O'Neill; Laura J. Zitur; Luis A. Fernandez; James M. Ntambi; Michael J. MacDonald
      Abstract: Publication date: Available online 11 February 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Israr-ul H. Ansari, Melissa J. Longacre, Scott W. Stoker, Mindy A. Kendrick, Lucas M. O'Neill, Laura J. Zitur, Luis A. Fernandez, James M. Ntambi, Michael J. MacDonald
      Long-chain acyl-CoA synthetases (ACSLs) convert fatty acids to fatty acyl-CoAs to regulate various physiologic processes. We characterized the ACSL isoforms in a cell line of homogeneous rat beta cells (INS-1832/13 cells) and human pancreatic islets. ACSL4 and ACSL3 proteins were present in the beta cells and human and rat pancreatic islets and concentrated in insulin secretory granules and less in mitochondria and negligible in other intracellular organelles. ACSL1 and ACSL6 proteins were not seen in INS-1832/13 cells or pancreatic islets. ACSL5 protein was seen only in INS-1832/13 cells. With shRNA-mediated gene silencing we developed stable ACSL knockdown cell lines from INS-1832/13 cells. Glucose-stimulated insulin release was inhibited ∼50% with ACSL4 and ACSL3 knockdown and unaffected in cell lines with knockdown of ACSL5, ACLS6 and ACSL1. Lentivirus shRNA-mediated gene silencing of ACSL4 and ACSL3 in human pancreatic islets inhibited glucose-stimulated insulin release. ACSL4 and ACSL3 knockdown cells showed inhibition of ACSL enzyme activity more with arachidonate than with palmitate as a substrate, consistent with their preference for unsaturated fatty acids as substrates. ACSL4 knockdown changed the patterns of fatty acids in phosphatidylserines and phosphatidylethanolamines. The results show the involvement of ACLS4 and ACLS3 in insulin secretion.

      PubDate: 2017-02-11T11:33:55Z
      DOI: 10.1016/
  • Mechanism of inhibition of botulinum neurotoxin type A light chain by two
           quinolinol compounds
    • Authors: Yacoba V.T. Minnow; Ronald Goldberg; Sreedhar R. Tummalapalli; David P. Rotella; Nina M. Goodey
      Abstract: Publication date: Available online 28 January 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Yacoba V.T. Minnow, Ronald Goldberg, Sreedhar R. Tummalapalli, David P. Rotella, Nina M. Goodey
      Quinolinol-based compounds are a promising starting point for discovery of effective inhibitors of the clostridial neurotoxin, botulinum neurotoxin type A light chain (BoNT/A LC). Insights into the mechanism of inhibition by quinolinol compounds facilitate interpretation of docking data and inhibitor optimization. In this study, a fluorogenic substrate of BoNT/A, SNAPtide, was used to study the mechanism by which two new quinolinol compounds, MSU58 and MSU84, with IC50 values of 3.3 μM and 5.8 μM, respectively, inhibit BoNT/A LC. Kinetic studies and model discrimination analysis showed both compounds to be competitive inhibitors of BoNT/A LC with inhibition constants (KI) 3.2 μM and 6.2 μM for MSU58 and MSU84, respectively. These data indicate that the inhibitors bind in the BoNT/A LC active site and that inhibitor binding is mutually exclusive with the binding of the substrate. This is the first study to report the competitive inhibition of BoNT/A LC by quinolinol compounds. These data help define the inhibitor binding pocket and, along with structure activity relationship studies, provide immediate direction for further compound synthesis.
      Graphical abstract image

      PubDate: 2017-01-29T17:41:45Z
      DOI: 10.1016/
  • Oligomerization affects the kinetics and thermodynamics of the interaction
           of a Bowman-Birk inhibitor with proteases
    • Authors: G.D. Brand; D.A.T. Pires; J.R. Furtado; A. Cooper; S.M. Freitas; C. Bloch
      Abstract: Publication date: Available online 26 January 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): G.D. Brand, D.A.T. Pires, J.R. Furtado, A. Cooper, S.M. Freitas, C. Bloch
      The black-eyed pea trypsin/chymotrypsin inhibitor (BTCI) forms concentration dependent homomultimers, as previously demonstrated by Light scattering and Atomic Force Microscopy. Considering that these self-aggregates might influence their binding to cognate enzymes, we investigated the interaction of BTCI at picomolar concentrations using surface immobilized Chymotrypsin (α-CT) and Trypsin (T) by Surface Plasmon Resonance. Our results indicate that BTCI has subnanomolar affinity to both immobilized enzymes, which is approximately two orders of magnitude higher than previously reported. Moreover, we probed the influence of temperature on protein binding equilibria in order to investigate their interaction energetics. While the BTCI/T interaction concurs with the canonical entropy-driven mechanism described for BBI interactions with serine proteinases, the BTCI/α-CT interaction does not. Our measurements indicate that bimolecular BTCI/α-CT complexes form with a negative enthalpy change and a moderate entropic increase. Direct calorimetric evaluation is in accord with the van't Hoff approximation obtained by SPR. We demonstrate that as protein concentrations increase to the micromolar range, secondary endothermic events become prevalent and affect both the kinetics and thermodynamics of protein associations. Our study reinforces that BBI interactions with serine proteinases should be studied in dilute solutions to abridge often neglected secondary interactions.

      PubDate: 2017-01-29T17:41:45Z
      DOI: 10.1016/
  • In vitro actin motility velocity varies linearly with the number of myosin
    • Authors: Y. Wang; T.P. Burghardt
      Abstract: Publication date: Available online 25 January 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Y. Wang, T.P. Burghardt
      Cardiac myosin is the motor powering the heart. It moves actin with 3 step-size varieties generated by torque from the myosin heavy chain lever-arm rotation under the influence of myosin essential light chain whose N-terminal extension binds actin. Proposed mechanisms adapting myosin mechanochemical characteristics on the fly sometimes involve modulation of step-size selection probability via motor strain sensitivity. Strain following the power stroke, hypothetically imposed by the finite actin detachment rate 1/ton, is shown to have no effect on unloaded velocity when multiple myosins are simultaneously strongly actin bound in an in vitro motility assay. Actin filaments slide ∼2 native step-sizes while more than 1 myosin strongly binds actin probably ruling out an actin detachment limited model for imposing strain. It suggests that single myosin estimates for ton are too large, not applicable to the ensemble situation, or both. Parallel motility data quantitation involving instantaneous particle velocities (frame velocity) and actin filament track averaged velocities (track velocity) give an estimate of the random walk step-size, δ. Comparing δ for slow and fast motility components suggests the higher speed component has cardiac myosin upshifting to longer steps. Variable step-size characteristics imply cardiac myosin maintains a velocity dynamic range not involving strain.
      Graphical abstract image

      PubDate: 2017-01-29T17:41:45Z
      DOI: 10.1016/
  • Specificity and mechanism of mandelamide hydrolase catalysis
    • Authors: S.A. Adediran; Pan-Fen Wang; Abbas G. Shilabin; Charles A. Baron; Michael J. McLeish; R.F.Pratt
      Abstract: Publication date: Available online 24 January 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): S.A. Adediran, Pan-Fen Wang, Abbas G. Shilabin, Charles A. Baron, Michael J. McLeish, R.F.Pratt
      The best-studied amidase signature (AS) enzyme is probably fatty acid amide hydrolase (FAAH). Closely related to FAAH is mandelamide hydrolase (MAH), whose substrate specificity and mechanism of catalysis are described in this paper. First, we developed a convenient chromogenic substrate, 4-nitrophenylacetamide, for MAH. The lack of reactivity of MAH with the corresponding ethyl ester confirmed the very limited size of the MAH leaving group site. The reactivity of MAH with 4-nitrophenyl acetate and methyl 4-nitrophenyl carbonate, therefore, suggested formation of an “inverse” acyl-enzyme where the small acyl-group occupies the normal leaving group site. We have interpreted the specificity of MAH for phenylacetamide substrates and small leaving groups in terms of its active site structure, using a homology model based on a FAAH crystal structure. The relevant structural elements were compared with those of FAAH. Phenylmethylboronic acid is a potent inhibitor of MAH (Ki = 27 nM), presumably because it forms a transition state analogue structure with the enzyme. O-Acyl hydroxamates were not irreversible inactivators of MAH but some were found to be transient inhibitors.
      Graphical abstract image

      PubDate: 2017-01-29T17:41:45Z
      DOI: 10.1016/
  • Introduction for the Special Issue on the Chemistry of Redox Signaling
    • Authors: Henry Jay Forman; Willem H. Koppenol
      Abstract: Publication date: Available online 11 January 2017
      Source:Archives of Biochemistry and Biophysics
      Author(s): Henry Jay Forman, Willem H. Koppenol

      PubDate: 2017-01-15T17:06:57Z
      DOI: 10.1016/
  • Peroxiredoxin 6 in the repair of peroxidized cell membranes and cell
    • Authors: Aron B. Fisher
      Abstract: Publication date: Available online 6 December 2016
      Source:Archives of Biochemistry and Biophysics
      Author(s): Aron B. Fisher
      Peroxiredoxin 6 represents a widely distributed group of peroxiredoxins that contain a single conserved cysteine in the protein monomer (1-cys Prdx). The cys when oxidized to the sulfenic form is reduced with glutathione (GSH) catalyzed by the π isoform of GSH-S-transferase. Three enzymatic activities of the protein have been described:1) peroxidase with H2O2, short chain hydroperoxides and phospholipid hydroperoxides as substrates; 2) phospholipase A2 (PLA2); and 3) lysophosphatidylcholine acyl transferase (LPCAT). These activities have important physiological roles in antioxidant defense, turnover of cellular phospholipids, and the generation of superoxide anion via initiation of the signaling cascade for activation of NADPH oxidase (type 2). The ability of Prdx6 to reduce peroxidized cell membrane phospholipids (peroxidase activity) and also to replace the oxidized sn-2 fatty acyl group through hydrolysis/reacylation (PLA2 and LPCAT activities) provides a complete system for the repair of peroxidized cell membranes.

      PubDate: 2016-12-08T01:10:59Z
      DOI: 10.1016/
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