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  Subjects -> MEDICAL SCIENCES (Total: 7272 journals)
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MEDICAL SCIENCES (1808 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 3562 Journals sorted alphabetically
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AADE in Practice     Hybrid Journal   (Followers: 4)
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Abia State University Medical Students' Association Journal     Full-text available via subscription  
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AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 8)
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Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 2)
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American Journal of Biomedical Engineering     Open Access   (Followers: 11)
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Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 4)
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Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
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Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 1)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
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Annals of Nigerian Medicine     Open Access   (Followers: 1)
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Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
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Applied Clinical Informatics     Hybrid Journal   (Followers: 2)
Applied Medical Informatics     Open Access   (Followers: 11)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
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Archive of Clinical Medicine     Open Access   (Followers: 1)
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Archives of Biomedical Sciences     Open Access   (Followers: 7)
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Archives of Trauma Research     Open Access   (Followers: 2)
Archivos de Medicina (Manizales)     Open Access  
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Arquivos de Ciências da Saúde     Open Access  
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ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 10)
Arterial Hypertension     Open Access  
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 12)
Artificial Organs     Hybrid Journal   (Followers: 1)
Asia Pacific Family Medicine     Open Access  
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 9)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 2)
Asian Journal of Cell Biology     Open Access   (Followers: 6)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 2)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 1)
Asian Journal of Scientific Research     Open Access   (Followers: 2)
Asian Journal of Transfusion Science     Open Access   (Followers: 2)
Asian Medicine     Hybrid Journal   (Followers: 4)
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Audiology - Communication Research     Open Access   (Followers: 8)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 2)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Aviation, Space, and Environmental Medicine     Full-text available via subscription   (Followers: 10)
Avicenna     Open Access   (Followers: 2)
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)
Bangladesh Journal of Anatomy     Open Access   (Followers: 1)
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Basic Sciences of Medicine     Open Access   (Followers: 2)
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BC Medical Journal     Free  
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Biologics in Therapy     Open Access  
Biology of Sex Differences     Open Access   (Followers: 3)

        1 2 3 4 5 6 7 8 | Last

Journal Cover Advances in Protein Chemistry and Structural Biology
  [SJR: 1.5]   [H-I: 62]   [20 followers]  Follow
    
   Full-text available via subscription Subscription journal
   ISSN (Online) 1876-1623
   Published by Elsevier Homepage  [3089 journals]
  • Chapter Six Enzymology of Microbial Dimethylsulfoniopropionate Catabolism
    • Authors: Mishtu Dey
      Pages: 195 - 222
      Abstract: Publication date: 2017
      Source:Advances in Protein Chemistry and Structural Biology, Volume 109
      Author(s): Mishtu Dey
      The biochemistry of dimethylsulfoniopropionate (DMSP) catabolism is reviewed. The microbes that catalyze the reactions central to DMSP catabolic pathways are described, and the focus is on the enzymology of the process. Approximately 109 tons of DMSP is released annually by marine eukaryotes as an osmolyte. A vast majority of DMSP is assimilated by bacteria through either a demethylation or lyase pathways, producing either the methane thiol or the volatile dimethylsulfide (DMS), respectively. Enzymatic breakdown of DMSP generates ~107 tons of DMS annually, which may have impact on global climate. DMS also acts as a chemoattractant for zooplanktons and seabirds. Both DMSP and DMS play a key role in the global sulfur cycle and are key nutrients for marine microbial growth. Important enzymes in the biochemical pathways of DMSP catabolism are covered in this review, with a focus on the latest developments in their mechanism.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.05.001
      Issue No: Vol. 109 (2017)
       
  • Human Interactomics: Comparative Analysis of Different Protein Interaction
           Resources and Construction of a Cancer Protein–Drug Bipartite Network
    • Authors: Javier De Las Rivas; Diego Alonso-López; Mónica M. Arroyo
      Abstract: Publication date: Available online 6 November 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Javier De Las Rivas, Diego Alonso-López, Mónica M. Arroyo
      Unraveling the protein interaction wiring that occurs in human cells as a scaffold of biological processes requires the identification of all elements that constitute such molecular interaction networks. Proteome-wide experimental studies and bioinformatic comprehensive efforts have provided reliable and updated compendiums of the human protein interactome. In this work, we present a current view of available databases of human protein–protein interactions (PPIs) that allow building protein interaction networks. We also investigate human proteins as targets of specific drugs to analyze how chemicals interact with different target proteins, placing also the study in a network relational space. Hence, we undertake a description of several major drug–target resources to provide a present perspective of the associations between human proteins and specific chemicals. The identification of molecular targets for specific drugs is a critical step to improve disease therapy. As different diseases have different biomolecular scenarios, we addressed the identification of drug-targeted genes focusing our investigations on cancer and cancer genes. So, a description of resources that provide curated compendiums of human cancer genes is presented. Cancer is a complex disease where multiple genetic changes rewire cellular networks during carcinogenesis. This indicates that cancer drug therapy needs the implementation of network-driven studies to reveal multiplex interactions between cancer genes and drugs. To make progress in this direction, in the last part of this work we provide a bipartite network of cancer genes and their drugs shown in a graph landscape that disclose the existence of specific drug–target modules.

      PubDate: 2017-11-11T22:41:41Z
      DOI: 10.1016/bs.apcsb.2017.09.002
       
  • Targeting Protein–Protein Interactions in the
           Ubiquitin–Proteasome Pathway
    • Authors: Maria Gaczynska; Pawel A. Osmulski
      Abstract: Publication date: Available online 18 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Maria Gaczynska, Pawel A. Osmulski
      The ubiquitin–proteasome pathway (UPP) is a major venue for controlled intracellular protein degradation in Eukaryota. The machinery of several hundred proteins is involved in recognizing, tagging, transporting, and cleaving proteins, all in a highly regulated manner. Short-lived transcription factors, misfolded translation products, stress-damaged polypeptides, or worn-out long-lived proteins, all can be found among the substrates of UPP. Carefully choreographed protein–protein interactions (PPI) are involved in each step of the pathway. For many of the steps small-molecule inhibitors have been identified and often they directly or indirectly target PPI. The inhibitors may destabilize intracellular proteostasis and trigger apoptosis. So far this is the most explored option used as an anticancer strategy. Alternatively, substrate-specific polyubiquitination may be regulated for a precise intervention aimed at a particular metabolic pathway. This very attractive opportunity is moving close to clinical application. The best known drug target in UPP is the proteasome: the end point of the journey of a protein destined for degradation. The proteasome alone is a perfect object to study the mechanisms and roles of PPI on many levels. This giant protease is built from multisubunit modules and additionally utilizes a service from transient protein ligands, for example, delivering substrates. An elaborate set of PPI within the highest-order proteasome assembly is involved in substrate recognition and processing. Below we will outline PPI involved in the UPP and discuss the growing prospects for their utilization in pharmacological interventions.

      PubDate: 2017-10-22T10:02:24Z
      DOI: 10.1016/bs.apcsb.2017.09.001
       
  • Investigating the Influence of Hotspot Mutations in Protein–Protein
           Interaction of IDH1 Homodimer Protein: A Computational Approach
    • Authors: D. Thirumal Kumar; P. Sneha; Jennifer Uppin; S. Usha; C. George Priya Doss
      Abstract: Publication date: Available online 14 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): D. Thirumal Kumar, P. Sneha, Jennifer Uppin, S. Usha, C. George Priya Doss
      Protein–protein interaction (PPI) helps in maintaining the cellular homeostasis. In particular, the homodimeric proteins play a crucial role as cell regulators. Studying the critical functions of each PPI on the living system is very challenging. The mutations in the PPIs have given birth to various diseases including many types of cancers and it has soon become the target for drug discovery. The mutations in IDH1, an asymmetric homodimer in the cytoplasm, leads to various diseases including gliomas. In this study, we have used extensive computational approaches to identify the impact of missense mutations (R132C, R132G, R132H, R132L, R132S, and V178I) occurring in the interacting region of the IDH1 homodimer. By in silico pathogenicity analysis, all the mutations occurring at the position 132 and 178 were found to be pathogenic and neutral. Furthermore, the mutants R132C and R132G were found to be responsible for increasing the stability, whereas the mutants R132H, R132L, and R132S were found to be responsible for the decrease in stability by stability analysis. R132H, R132L, and R132S mutants exhibited higher destabilization when compared to the structures of R132C and R132G mutants by molecular docking and molecular dynamics analysis.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.08.002
       
  • Computational Resources for Predicting Protein–Protein Interactions
    • Authors: Himani Tanwar; C. George Priya Doss
      Abstract: Publication date: Available online 12 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Himani Tanwar, C. George Priya Doss
      Proteins are the essential building blocks and functional components of a cell. They account for the vital functions of an organism. Proteins interact with each other and form protein interaction networks. These protein interactions play a major role in all the biological processes and pathways. The previous methods of predicting protein interactions were experimental which focused on a small set of proteins or a particular protein. However, these experimental approaches are low-throughput as they are time-consuming and require a significant amount of human effort. This led to the development of computational techniques that uses high-throughput experimental data for analyzing protein–protein interactions. The main purpose of this review is to provide an overview on the computational advancements and tools for the prediction of protein interactions. The major databases for the deposition of these interactions are also described. The advantages, as well as the specific limitations of these tools, are highlighted which will shed light on the computational aspects that can help the biologist and researchers in their research.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.07.006
       
  • Probing the Protein–Protein Interaction Network of Proteins Causing
           Maturity Onset Diabetes of the Young
    • Authors: P. Sneha; D. Thirumal Kumar; Jose Lijo; M. Megha; R. Siva; C. George Priya Doss
      Abstract: Publication date: Available online 10 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): P. Sneha, D. Thirumal Kumar, Jose Lijo, M. Megha, R. Siva, C. George Priya Doss
      Protein–protein interactions (PPIs) play vital roles in various cellular pathways. Most of the proteins perform their responsibilities by interacting with an enormous number of proteins. Understanding these interactions of the proteins and their interacting partners has shed light toward the field of drug discovery. Also, PPIs enable us to understand the functions of a protein by understanding their interacting partners. Consequently, in the current study, PPI network of the proteins causing MODY (Maturity Onset Diabetes of the Young) was drawn, and their correlation in causing a disease condition was marked. MODY is a monogenic type of diabetes caused by autosomal dominant inheritance. Extensive research on transcription factor and their corresponding genetic pathways have been studied over the last three decades, yet, very little is understood about the molecular modalities of highly dynamic interactions between transcription factors, genomic DNA, and the protein partners. The current study also reveals the interacting patterns of the various transcription factors. Consequently, in the current work, we have devised a PPI analysis to understand the plausible pathway through which the protein leads to a deformity in glucose uptake.

      PubDate: 2017-10-14T02:06:25Z
      DOI: 10.1016/bs.apcsb.2017.07.004
       
  • Multifaceted Nucleolin Protein and Its Molecular Partners in Oncogenesis
    • Authors: Iva Ugrinova; Maria Petrova Mounira Chalabi-Dchar Philippe Bouvet
      Abstract: Publication date: Available online 6 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Iva Ugrinova, Maria Petrova, Mounira Chalabi-Dchar, Philippe Bouvet
      Discovered in 1973, nucleolin is one of the most abundant phosphoproteins of the nucleolus. The ability of nucleolin to be involved in many cellular processes is probably related to its structural organization and its capability to form many different interactions with other proteins. Many functions of nucleolin affect cellular processes involved in oncogenesis—for instance: in ribosome biogenesis; in DNA repair, remodeling, and genome stability; in cell division and cell survival; in chemokine and growth factor signaling pathways; in angiogenesis and lymphangiogenesis; in epithelial–mesenchymal transition; and in stemness. In this review, we will describe the different functions of nucleolin in oncogenesis through its interaction with other proteins.

      PubDate: 2017-10-08T20:41:03Z
       
  • Homo- and Heterodimerization of Proteins in Cell Signaling: Inhibition and
           Drug Design
    • Authors: Sitanshu Singh; Seetharama Jois
      Abstract: Publication date: Available online 6 October 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Sitanshu S. Singh, Seetharama D. Jois
      Protein dimerization controls many physiological processes in the body. Proteins form homo-, hetero-, or oligomerization in the cellular environment to regulate the cellular processes. Any deregulation of these processes may result in a disease state. Protein–protein interactions (PPIs) can be inhibited by antibodies, small molecules, or peptides, and inhibition of PPI has therapeutic value. PPI drug discovery research has steadily increased in the last decade, and a few PPI inhibitors have already reached the pharmaceutical market. Several PPI inhibitors are in clinical trials. With advancements in structural and molecular biology methods, several methods are now available to study protein homo- and heterodimerization and their inhibition by drug-like molecules. Recently developed methods to study PPI such as proximity ligation assay and enzyme-fragment complementation assay that detect the PPI in the cellular environment are described with examples. At present, the methods used to design PPI inhibitors can be classified into three major groups: (1) structure-based drug design, (2) high-throughput screening, and (3) fragment-based drug design. In this chapter, we have described some of the experimental methods to study PPIs and their inhibition. Examples of homo- and heterodimers of proteins, their structural and functional aspects, and some of the inhibitors that have clinical importance are discussed. The design of PPI inhibitors of epidermal growth factor receptor heterodimers and CD2–CD58 is discussed in detail.

      PubDate: 2017-10-08T20:41:03Z
       
  • Analysis of Protein Interactions by Surface Plasmon Resonance
    • Authors: Dennis G. Drescher; Dakshnamurthy Selvakumar; Marian J. Drescher
      Abstract: Publication date: Available online 12 September 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Dennis G. Drescher, Dakshnamurthy Selvakumar, Marian J. Drescher
      Surface plasmon resonance is an optical technique that is utilized for detecting molecular interactions, such as interactions that occur between proteins or other classes of molecules. Binding of a mobile molecule (analyte) to a molecule immobilized on a thin metal film (ligand) changes the refractive index of the film. The angle of extinction of light that is completely reflected after polarized light impinges upon the film, is altered and monitored as a change in detector position for a dip in reflected intensity (the surface plasmon resonance phenomenon). Because the method strictly detects mass, there is no need to label the interacting components, thus eliminating possible changes of their molecular properties. In this chapter, we review essential SPR methodology and present applications to basic science and human disease.

      PubDate: 2017-09-18T04:43:08Z
      DOI: 10.1016/bs.apcsb.2017.07.003
       
  • Using TR-FRET to Investigate Protein–Protein Interactions: A Case Study
           of PXR-Coregulator Interaction
    • Authors: Wenwei Lin; Taosheng Chen
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Wenwei Lin, Taosheng Chen
      Time-resolved fluorescence resonance energy transfer (TR-FRET) protein–protein interaction assays, especially in the format of receptor coregulator (coactivator and corepressor) recruitment/repression assays, have been widely used in nuclear receptor research to characterize the modes of action, efficacies, and binding affinities of ligands (including their properties as agonists, antagonists, and inverse agonists). However, there has been only limited progress in using this assay format for pregnane X receptor (PXR). In this chapter, we discuss TR-FRET protein–protein interaction assays and focus on a novel PXR TR-FRET coactivator interaction assay that we have developed based on a PXR coactivator cocrystal study. This new PXR TR-FRET coactivator interaction assay can characterize the binding affinities of PXR ligands and also differentiate antagonists from agonists. This assay is very robust, with the signal remaining stable over a long incubation time (up to 300min has been tested). It can tolerate high concentrations of DMSO (up to 5%) and has a high signal-to-noise ratio (six under typical assay conditions). This newly developed PXR TR-FRET coactivator interaction assay has potential application in high-throughput screening to identify and characterize novel PXR agonists and antagonists.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.001
       
  • Structural Prediction of Protein–Protein Interactions by Docking:
           Application to Biomedical Problems
    • Authors: Didier Barradas-Bautista; Mireia Rosell; Chiara Pallara; Juan Fernández-Recio
      Abstract: Publication date: Available online 31 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Didier Barradas-Bautista, Mireia Rosell, Chiara Pallara, Juan Fernández-Recio
      A huge amount of genetic information is available thanks to the recent advances in sequencing technologies and the larger computational capabilities, but the interpretation of such genetic data at phenotypic level remains elusive. One of the reasons is that proteins are not acting alone, but are specifically interacting with other proteins and biomolecules, forming intricate interaction networks that are essential for the majority of cell processes and pathological conditions. Thus, characterizing such interaction networks is an important step in understanding how information flows from gene to phenotype. Indeed, structural characterization of protein–protein interactions at atomic resolution has many applications in biomedicine, from diagnosis and vaccine design, to drug discovery. However, despite the advances of experimental structural determination, the number of interactions for which there is available structural data is still very small. In this context, a complementary approach is computational modeling of protein interactions by docking, which is usually composed of two major phases: (i) sampling of the possible binding modes between the interacting molecules and (ii) scoring for the identification of the correct orientations. In addition, prediction of interface and hot-spot residues is very useful in order to guide and interpret mutagenesis experiments, as well as to understand functional and mechanistic aspects of the interaction. Computational docking is already being applied to specific biomedical problems within the context of personalized medicine, for instance, helping to interpret pathological mutations involved in protein–protein interactions, or providing modeled structural data for drug discovery targeting protein–protein interactions.

      PubDate: 2017-09-05T23:52:57Z
      DOI: 10.1016/bs.apcsb.2017.06.003
       
  • Development of Protein–Protein Interaction Inhibitors for the
           Treatment of Infectious Diseases
    • Authors: Andrew F. Voter; James L. Keck
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew F. Voter, James L. Keck
      Protein–protein interaction (PPI) inhibitors are a rapidly expanding class of therapeutics. Recent advances in our understanding of PPIs and success of early examples of PPI inhibitors demonstrate the feasibility of targeting PPIs. This review summarizes the techniques used for the discovery and optimization of a diverse set PPI inhibitors, focusing on the development of PPI inhibitors as new antibacterial and antiviral agents. We close with a summary of the advances responsible for making PPI inhibitors realistic targets for therapeutic intervention and brief outlook of the field.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.005
       
  • Subcellular Targeting of Nitric Oxide Synthases Mediated by Their
           N-Terminal Motifs
    • Authors: Carlos Costas-Insua; Javier Merino-Gracia; Clara Aicart-Ramos; Ignacio Rodríguez-Crespo
      Abstract: Publication date: Available online 24 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Carlos Costas-Insua, Javier Merino-Gracia, Clara Aicart-Ramos, Ignacio Rodríguez-Crespo
      From a catalytic point of view, the three mammalian nitric oxide synthases (NOSs) function in an almost identical way. The N-terminal oxygenase domain catalyzes the conversion of l-arginine to l-citrulline plus ·NO in two sequential oxidation steps. Once l-arginine binds to the active site positioned above the heme moiety, two consecutive monooxygenation reactions take place. In the first step, l-arginine is hydroxylated to make Nω-hydroxy-l-arginine in a process that requires 1 molecule of NADPH and 1 molecule of O2 per mol of l-arginine reacted. In the second step, Nω-hydroxy-l-arginine, never leaving the active site, is oxidized to ·NO plus l-citrulline and 1 molecule of O2 and 0.5 molecules of NADPH are consumed. Since nitric oxide is an important signaling molecule that participates in a number of biological processes, including neurotransmission, vasodilation, and immune response, synthesis and release of ·NO in vivo must be exquisitely regulated both in time and in space. Hence, NOSs have evolved introducing in their amino acid sequences subcellular targeting motifs, most of them located at their N-termini. Deletion studies performed on recombinant, purified NOSs have revealed that part of the N-terminus of all three NOS can be eliminated with the resulting mutant enzymes still being catalytically active. Likewise, NOS isoforms lacking part of their N-terminus when transfected in cells render mislocalized, active proteins. In this review we will comment on the current knowledge of these subcellular targeting signals present in nNOS, iNOS, and eNOS.

      PubDate: 2017-08-29T21:00:12Z
      DOI: 10.1016/bs.apcsb.2017.07.002
       
  • Targeting the Architecture of Deregulated Protein Complexes in Cancer
    • Authors: Eduard Stefan; Jakob Troppmair; Klaus Bister
      Abstract: Publication date: Available online 18 August 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Eduard Stefan, Jakob Troppmair, Klaus Bister
      The architectures of central signaling hubs are precisely organized by static and dynamic protein–protein interactions (PPIs). Upon deregulation, these PPI platforms are capable to propagate or initiate pathophysiological signaling events. This causes the acquisition of molecular features contributing to the etiology or progression of many diseases, including cancer, where deregulated molecular interactions of signaling proteins have been best studied. The reasons for PPI-dependent reprogramming of cancer-initiating cells are manifold; in many cases, mutations perturb PPIs, enzyme activities, protein abundance, or protein localization. Consequently, the pharmaceutical targeting of PPIs promises to be of remarkable therapeutic value. For this review we have selected three key players of oncogenic signaling which are differently affected by PPI deregulation: two (the small G proteins of the RAS family and the transcription factor MYC) are considered “undruggable” using classical drug discovery approaches and in the case of the third protein discussed here, PKA, standard kinase inhibitors, may be unsuitable in the clinic. These circumstances require alternative strategies, which may lie in pharmaceutical drug interference of critical PPIs accountable for oncogenic signaling.

      PubDate: 2017-08-18T16:55:48Z
      DOI: 10.1016/bs.apcsb.2017.07.001
       
  • Protein–Protein Interaction Modulators for Epigenetic Therapies
    • Authors: Bárbara I. Díaz-Eufracio; J. Jesús Naveja; José L. Medina-Franco
      Abstract: Publication date: Available online 25 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Bárbara I. Díaz-Eufracio, J. Jesús Naveja, José L. Medina-Franco
      Targeting protein–protein interactions (PPIs) is becoming an attractive approach for drug discovery. This is particularly true for difficult or emerging targets, such as epitargets that may be elusive to drugs that fall into the traditional chemical space. The chemical nature of the PPIs makes attractive the use of peptides or peptidomimetics to selectively modulate such interactions. Despite the fact peptide-based drug discovery has been challenging, the use of peptides as leads compounds for drug discovery is still a valid strategy. This chapter discusses the current status of PPIs in epigenetic drug discovery. A special emphasis is made on peptides and peptide-like compounds as potential drug candidates.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.002
       
  • Intrinsic Disorder, Protein–Protein Interactions, and Disease
    • Authors: Vladimir N. Uversky
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Vladimir N. Uversky
      It is recognized now that biologically active proteins without stable tertiary structure (known as intrinsically disordered proteins, IDPs) and hybrid proteins containing ordered domains and intrinsically disordered protein regions (IDPRs) are important players found in any given proteome. These IDPs/IDPRs possess functions that complement functional repertoire of their ordered counterparts, being commonly related to recognition, as well as control and regulation of various signaling pathways. They are interaction masters, being able to utilize a wide spectrum of interaction mechanisms, ranging from induced folding to formation of fuzzy complexes where significant levels of disorder are preserved, to polyvalent stochastic interactions playing crucial roles in the liquid–liquid phase transitions leading to the formation of proteinaceous membrane-less organelles. IDPs/IDPRs are tightly controlled themselves via various means, including alternative splicing, precisely controlled expression and degradation, binding to specific partners, and posttranslational modifications. Distortions in the regulation and control of IDPs/IDPRs, as well as their aberrant interactivity are commonly associated with various human diseases. This review presents some aspects of the intrinsic disorder-based functionality and dysfunctionality, paying special attention to the normal and pathological protein–protein interactions.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.005
       
  • Targeting Intramembrane Protein–Protein Interactions: Novel Therapeutic
           Strategy of Millions Years Old
    • Authors: Alexander B. Sigalov
      Abstract: Publication date: Available online 24 July 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alexander B. Sigalov
      Intramembrane protein–protein interactions (PPIs) are involved in transmembrane signal transduction mediated by cell surface receptors and play an important role in health and disease. Recently, receptor-specific modulatory peptides rationally designed using a general platform of transmembrane signaling, the signaling chain homooligomerization (SCHOOL) model, have been proposed to therapeutically target these interactions in a variety of serious diseases with unmet needs including cancer, sepsis, arthritis, retinopathy, and thrombosis. These peptide drug candidates use ligand-independent mechanisms of action (SCHOOL mechanisms) and demonstrate potent efficacy in vitro and in vivo. Recent studies surprisingly revealed that in order to modify and/or escape the host immune response, human viruses use similar mechanisms and modulate cell surface receptors by targeting intramembrane PPIs in a ligand-independent manner. Here, I review these intriguing mechanistic similarities and discuss how the viral strategies optimized over a billion years of the coevolution of viruses and their hosts can help to revolutionize drug discovery science and develop new, disruptive therapies. Examples are given.

      PubDate: 2017-07-29T09:19:22Z
      DOI: 10.1016/bs.apcsb.2017.06.004
       
  • A Paradigm for CH Bond Cleavage: Structural and Functional Aspects of
           Transition State Stabilization by Mandelate Racemase
    • Authors: Stephen L. Bearne; Martin St. Maurice
      Abstract: Publication date: Available online 9 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Stephen L. Bearne, Martin St. Maurice
      Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent, 1,1-proton transfer reaction that racemizes (R)- and (S)-mandelate. MR shares a partial reaction (i.e., the metal ion-assisted, Brønsted base-catalyzed proton abstraction of the α-proton of carboxylic acid substrates) and structural features ((β/α)7β-barrel and N-terminal α + β capping domains) with a vast group of homologous, yet functionally diverse, enzymes in the enolase superfamily. Mechanistic and structural studies have developed this enzyme into a paradigm for understanding how enzymes such as those of the enolase superfamily overcome kinetic and thermodynamic barriers to catalyze the abstraction of an α-proton from a carbon acid substrate with a relatively high pK a value. Structural studies on MR bound to intermediate/transition state analogues have delineated those structural features that MR uses to stabilize transition states and enhance reaction rates of proton abstraction. Kinetic, site-directed mutagenesis, and structural studies have also revealed that the phenyl ring of the substrate migrates through the hydrophobic cavity within the active site during catalysis and that the Brønsted acid–base catalysts (Lys 166 and His 297) may be utilized as binding determinants for inhibitor recognition. In addition, structural studies on the adduct formed from the irreversible inhibition of MR by 3-hydroxypyruvate revealed that MR can form and deprotonate a Schiff-base with 3-hydroxypyruvate to yield an enol(ate)-aldehyde adduct, suggesting a possible evolutionary link between MR and the Schiff-base forming aldolases. As the archetype of the enolase superfamily, mechanistic and structural studies on MR will continue to enhance our understanding of enzyme catalysis and furnish insights into the evolution of enzyme function.

      PubDate: 2017-06-13T07:14:51Z
      DOI: 10.1016/bs.apcsb.2017.04.007
       
  • Sortase Transpeptidases: Structural Biology and Catalytic Mechanism
    • Authors: Alex W. Jacobitz; Michele D. Kattke; Jeff Wereszczynski; Robert T. Clubb
      Abstract: Publication date: Available online 5 June 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Alex W. Jacobitz, Michele D. Kattke, Jeff Wereszczynski, Robert T. Clubb
      Gram-positive bacteria use sortase cysteine transpeptidase enzymes to covalently attach proteins to their cell wall and to assemble pili. In pathogenic bacteria sortases are potential drug targets, as many of the proteins that they display on the microbial surface play key roles in the infection process. Moreover, the Staphylococcus aureus Sortase A (SaSrtA) enzyme has been developed into a valuable biochemical reagent because of its ability to ligate biomolecules together in vitro via a covalent peptide bond. Here we review what is known about the structures and catalytic mechanism of sortase enzymes. Based on their primary sequences, most sortase homologs can be classified into six distinct subfamilies, called class A–F enzymes. Atomic structures reveal unique, class-specific variations that support alternate substrate specificities, while structures of sortase enzymes bound to sorting signal mimics shed light onto the molecular basis of substrate recognition. The results of computational studies are reviewed that provide insight into how key reaction intermediates are stabilized during catalysis, as well as the mechanism and dynamics of substrate recognition. Lastly, the reported in vitro activities of sortases are compared, revealing that the transpeptidation activity of SaSrtA is at least 20-fold faster than other sortases that have thus far been characterized. Together, the results of the structural, computational, and biochemical studies discussed in this review begin to reveal how sortases decorate the microbial surface with proteins and pili, and may facilitate ongoing efforts to discover therapeutically useful small molecule inhibitors.

      PubDate: 2017-06-08T06:29:55Z
      DOI: 10.1016/bs.apcsb.2017.04.008
       
  • Computational Biochemistry—Enzyme Mechanisms Explored
    • Authors: Martin Culka; Florian Gisdon Matthias Ullmann
      Abstract: Publication date: Available online 27 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Martin Culka, Florian J. Gisdon, G. Matthias Ullmann
      Understanding enzyme mechanisms is a major task to achieve in order to comprehend how living cells work. Recent advances in biomolecular research provide huge amount of data on enzyme kinetics and structure. The analysis of diverse experimental results and their combination into an overall picture is, however, often challenging. Microscopic details of the enzymatic processes are often anticipated based on several hints from macroscopic experimental data. Computational biochemistry aims at creation of a computational model of an enzyme in order to explain microscopic details of the catalytic process and reproduce or predict macroscopic experimental findings. Results of such computations are in part complementary to experimental data and provide an explanation of a biochemical process at the microscopic level. In order to evaluate the mechanism of an enzyme, a structural model is constructed which can be analyzed by several theoretical approaches. Several simulation methods can and should be combined to get a reliable picture of the process of interest. Furthermore, abstract models of biological systems can be constructed combining computational and experimental data. In this review, we discuss structural computational models of enzymatic systems. We first discuss various models to simulate enzyme catalysis. Furthermore, we review various approaches how to characterize the enzyme mechanism both qualitatively and quantitatively using different modeling approaches.

      PubDate: 2017-05-29T05:07:08Z
       
  • Striking Diversity in Holoenzyme Architecture and Extensive Conformational
           Variability in Biotin-Dependent Carboxylases
    • Authors: Liang Tong
      Abstract: Publication date: Available online 23 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Liang Tong
      Biotin-dependent carboxylases are widely distributed in nature and have central roles in the metabolism of fatty acids, amino acids, carbohydrates, and other compounds. The last decade has seen the accumulation of structural information on most of these large holoenzymes, including the 500-kDa dimeric yeast acetyl-CoA carboxylase, the 750-kDa α6β6 dodecameric bacterial propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and geranyl-CoA carboxylase, the 720-kDa hexameric bacterial long-chain acyl-CoA carboxylase, the 500-kDa tetrameric bacterial single-chain pyruvate carboxylase, the 370-kDa α2β4 bacterial two-subunit pyruvate carboxylase, and the 130-kDa monomeric eukaryotic urea carboxylase. A common theme that has emerged from these studies is the dramatic structural flexibility of these holoenzymes despite their strong overall sequence conservation, evidenced both by the extensive diversity in the architectures of the holoenzymes and by the extensive conformational variability of their domains and subunits. This structural flexibility is crucial for the function and regulation of these enzymes and identifying compounds that can interfere with it represents an attractive approach for developing novel modulators and drugs. The extensive diversity observed in the structures so far and its biochemical and functional implications will be the focus of this review.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.006
       
  • Mechanistic Insights Into Catalytic RNA–Protein Complexes Involved in
           Translation of the Genetic Code
    • Authors: Satya B. Routh; Rajan Sankaranarayanan
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Satya B. Routh, Rajan Sankaranarayanan
      The contemporary world is an “RNA–protein world” rather than a “protein world” and tracing its evolutionary origins is of great interest and importance. The different RNAs that function in close collaboration with proteins are involved in several key physiological processes, including catalysis. Ribosome—the complex megadalton cellular machinery that translates genetic information encoded in nucleotide sequence to amino acid sequence—epitomizes such an association between RNA and protein. RNAs that can catalyze biochemical reactions are known as ribozymes. They usually employ general acid–base catalytic mechanism, often involving the 2′-OH of RNA that activates and/or stabilizes a nucleophile during the reaction pathway. The protein component of such RNA–protein complexes (RNPCs) mostly serves as a scaffold which provides an environment conducive for the RNA to function, or as a mediator for other interacting partners. In this review, we describe those RNPCs that are involved at different stages of protein biosynthesis and in which RNA performs the catalytic function; the focus of the account is on highlighting mechanistic aspects of these complexes. We also provide a perspective on such associations in the context of proofreading during translation of the genetic code. The latter aspect is not much appreciated and recent works suggest that this is an avenue worth exploring, since an understanding of the subject can provide useful insights into how RNAs collaborate with proteins to ensure fidelity during these essential cellular processes. It may also aid in comprehending evolutionary aspects of such associations.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.002
       
  • Computational Glycobiology: Mechanistic Studies of Carbohydrate-Active
           Enzymes and Implication for Inhibitor Design
    • Authors: Andrew P. Montgomery; Kela Xiao; Xingyong Wang; Danielle Skropeta; Haibo Yu
      Abstract: Publication date: Available online 19 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Andrew P. Montgomery, Kela Xiao, Xingyong Wang, Danielle Skropeta, Haibo Yu
      Carbohydrate-active enzymes (CAZymes) are families of essential and structurally related enzymes, which catalyze the creation, modification, and degradation of glycosidic bonds in carbohydrates to maintain essentially all kingdoms of life. CAZymes play a key role in many biological processes underpinning human health and diseases (e.g., cancer, diabetes, Alzheimer's diseases, AIDS) and have thus emerged as important drug targets in the fight against pathogenesis. The realization of the full potential of CAZymes remains a significant challenge, relying on a deeper understanding of the molecular mechanisms of catalysis. Considering numerous unsettled questions in the literature, while with a large amount of structural, kinetic, and mutagenesis data available for CAZymes, there is a pressing need and an abundant opportunity for collaborative computational and experimental investigations with the aim to unlock the secrets of CAZyme catalysis at an atomic level. In this review, we briefly survey key methodology development in computational studies of CAZyme catalysis. This is complemented by selected case studies highlighting mechanistic insights provided by computational glycobiology. Implication for inhibitor design by mimicking the transition state is also illustrated for both glycoside hydrolases and glycosyltransferases. The challenges for such studies will be noted and finally an outlook for future directions will be provided.

      PubDate: 2017-05-24T04:47:30Z
      DOI: 10.1016/bs.apcsb.2017.04.003
       
  • Biology, Mechanism, and Structure of Enzymes in the
           α-d-Phosphohexomutase Superfamily
    • Authors: Kyle M. Stiers; Andrew G. Muenks; Lesa J. Beamer
      Abstract: Publication date: Available online 17 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Kyle M. Stiers, Andrew G. Muenks, Lesa J. Beamer
      Enzymes in the α-d-phosphohexomutases superfamily catalyze the reversible conversion of phosphosugars, such as glucose 1-phosphate and glucose 6-phosphate. These reactions are fundamental to primary metabolism across the kingdoms of life and are required for a myriad of cellular processes, ranging from exopolysaccharide production to protein glycosylation. The subject of extensive mechanistic characterization during the latter half of the 20th century, these enzymes have recently benefitted from biophysical characterization, including X-ray crystallography, NMR, and hydrogen–deuterium exchange studies. This work has provided new insights into the unique catalytic mechanism of the superfamily, shed light on the molecular determinants of ligand recognition, and revealed the evolutionary conservation of conformational flexibility. Novel associations with inherited metabolic disease and the pathogenesis of bacterial infections have emerged, spurring renewed interest in the long-appreciated functional roles of these enzymes.

      PubDate: 2017-05-19T03:29:24Z
      DOI: 10.1016/bs.apcsb.2017.04.005
       
  • Collagenolytic Matrix Metalloproteinase Structure–Function
           Relationships: Insights From Molecular Dynamics Studies
    • Authors: Tatyana G. Karabencheva-Christova; Christo Z. Christov; Gregg B. Fields
      Abstract: Publication date: Available online 8 May 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Tatyana G. Karabencheva-Christova, Christo Z. Christov, Gregg B. Fields
      Several members of the zinc-dependent matrix metalloproteinase (MMP) family catalyze collagen degradation. Experimental data reveal a collaboration between different MMP domains in order to achieve efficient collagenolysis. Molecular dynamics (MD) simulations have been utilized to provide atomistic details of the collagenolytic process. The triple-helical structure of collagen exhibits local regions of flexibility, with modulation of interchain salt bridges and water bridges contributing to accessibility of individual chains by the enzyme. In turn, the hemopexin-like (HPX) domain of the MMP initially binds the triple helix and facilitates the presentation of individual strands to active site in the catalytic (CAT) domain. Extensive positive and negative correlated motions are observed between the CAT and HPX domains when collagen is bound. Ultimately, the MD simulation studies have complemented structural (NMR spectroscopy, X-ray crystallography) and kinetic analyses to provide a more detailed mechanistic view of MMP-catalyzed collagenolysis.

      PubDate: 2017-05-14T01:16:32Z
      DOI: 10.1016/bs.apcsb.2017.04.001
       
  • Stress-Induced NLRP3 Inflammasome in Human Diseases
    • Authors: Elísabet Alcocer-Gómez; Beatriz Castejón-Vega; Mario D. Cordero
      Abstract: Publication date: Available online 27 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Elísabet Alcocer-Gómez, Beatriz Castejón-Vega, Mario D. Cordero
      Stress is a complex event that induces disturbances to physiological and psychological homeostasis, and it may have a detrimental impact on certain brain and physiological functions. In the last years, a dual role of the stress effect has been studied in order to elucidate the molecular mechanism by which can induce physiological symptoms after psychological stress exposition and vice versa. In this sense, inflammation has been proposed as an important starring. And in the same line, the inflammasome complex has emerged to give responses because of its role of stress sensor. The implication of the same complex, NLRP3 inflammasome, in different diseases such as cardiovascular, neurodegenerative, psychiatric, and metabolic diseases opens a door to develop new therapeutic perspectives.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.02.002
       
  • A Computational Approach to Identify the Biophysical and Structural
           Aspects of Methylenetetrahydrofolate Reductase (MTHFR) Mutations (A222V,
           E429A, and R594Q) Leading to Schizophrenia
    • Authors: Himani Tanwar; P. Sneha; D. Thirumal Kumar; R. Siva; Charles Emmanuel Jebaraj Walter; C. George Priya Doss
      Abstract: Publication date: Available online 23 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Himani Tanwar, P. Sneha, D. Thirumal Kumar, R. Siva, Charles Emmanuel Jebaraj Walter, C. George Priya Doss
      The association between depression and methylenetetrahydrofolate reductase (MTHFR) has been continually demonstrated in clinical studies, yet there are sparse resources available to build a relationship between the mutations associated with MTHFR and depression. The common mutations found to be associated with schizophrenia and MTHFR are A222V, E429A, and R594Q. Although abundant research on structural and functional effects caused by A222V mutation is available, very less amount of studies have been done on the other two mutants (E429A and R594Q). Hence in this study, a comparative analysis was carried out between the most common A222V mutation, a prevalent E429A mutation, and a less prevalent and less deleterious R594Q mutation. To predict structural rearrangements upon mutation, we proposed a computational pipeline using in silico prediction tools, molecular docking, and molecular dynamics simulation analysis. Since the association of flavin adenine dinucleotide (FAD) is important for the functioning of the protein, binding analysis between protein and the coenzyme was performed. This would enable us to understand the interference level of each mutation over FAD-binding activity. Consequently, we found that two mutations (A222V and E429A) showed lesser binding activity and structural deviations when compared to the native molecule and mutant R594Q. Comparatively, higher structural changes were observed with A222V mutant complex in comparison to other mutant complexes. Computational studies like this could render better insights into the structural changes in the protein and their relationship with the disease condition.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.01.007
       
  • Neuroinflammation in Alzheimer's Disease: The Preventive and Therapeutic
           Potential of Polyphenolic Nutraceuticals
    • Authors: Yousef Sawikr; Nagendra Sastry Yarla; Ilaria Peluso; Mohammad Amjad Kamal; Gjumrakch Aliev; Anupam Bishayee
      Abstract: Publication date: Available online 22 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Yousef Sawikr, Nagendra Sastry Yarla, Ilaria Peluso, Mohammad Amjad Kamal, Gjumrakch Aliev, Anupam Bishayee
      Brain inflammation, characterized by increased microglia and astrocyte activation, increases during aging and is a key feature of neurodegenerative diseases, such as Alzheimer's disease (AD). In AD, neuronal death and synaptic impairment, induced by amyloid-β (Aβ) peptide, are at least in part mediated by microglia and astrocyte activation. Glial activation results in the sustained production of proinflammatory cytokines and reactive oxygen species, giving rise to a chronic inflammatory process. Astrocytes are the most abundant glial cells in the central nervous system and are involved in the neuroinflammation. Astrocytes can be activated by numerous factors, including free saturated fatty acids, pathogens, lipopolysaccharide, and oxidative stress. Activation of astrocytes produces inflammatory cytokines and the enzyme cyclooxygenase-2, enhancing the production of Aβ. Furthermore, the role of the receptor for advanced glycation end products/nuclear factor-κB (NF-κB) axis in neuroinflammation is in line with the nonenzymatic glycosylation theory of aging, suggesting a central role of the advanced glycation end products in the age-related cognitive and a possible role of nutraceuticals in the prevention of neuroinflammation and AD. However, modulation of P-glycoprotein, rather than antioxidant and anti-inflammatory effects, could be the major mechanism of polyphenolic compounds, including flavonoids. Curcumin, resvertrol, piperine, and other polyphenols have been explored as novel therapeutic and preventive agents for AD. The aim of this review is to critically analyze and discuss the mechanisms involved in neuroinflammation and the possible role of nutraceuticals in the prevention and therapy of AD by targeting neuroinflammation.

      PubDate: 2017-03-28T20:30:18Z
      DOI: 10.1016/bs.apcsb.2017.02.001
       
  • Analyzing the Effect of V66M Mutation in BDNF in Causing Mood Disorders: A
           Computational Approach
    • Authors: Sneha Thirumal; Kumar Sugandhi Saini Kreeti Kajal Magesh Siva George
      Abstract: Publication date: Available online 9 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): P. Sneha, D. Thirumal Kumar, Sugandhi Saini, Kreeti Kajal, R. Magesh, R. Siva, C. George Priya Doss
      Mental disorders or mood disorders are prevalent globally irrespective of region, race, and ethnic groups. Of the types of mood disorders, major depressive disorder (MDD) and bipolar disorder (BPD) are the most prevalent forms of psychiatric condition. A number of preclinical studies emphasize the essential role of brain-derived neurotrophic factor (BDNF) in the pathophysiology of mood disorders. Additionally, BDNF is the most common growth factor in the central nervous system along with their essential role during the neural development and the synaptic elasticity. A malfunctioning of this protein is associated with many types of mood disorders. The variant methionine replaces valine at 66th position is strongly related to BPD, and an individual with a homozygous condition of this allele is at a greater risk of developing MDD. There are very sparse reports suggesting the structural changes of the protein occurring upon the mutation. Consequently, in this study, we applied a computational pipeline to understand the effects caused by the mutation on the protein's structure and function. With the use of in silico tools and computational macroscopic methods, we identified a decrease in the alpha-helix nature, and an overall increase in the random coils that could have probably resulted in deformation of the protein.

      PubDate: 2017-03-09T16:01:25Z
       
  • Oxidative Stress: Love and Hate History in Central Nervous System
    • Authors: Genaro Gabriel Ortiz; Fermín P. Pacheco Moisés; Mario Mireles-Ramírez; Luis J. Flores-Alvarado; Héctor González-Usigli; Víctor J. Sánchez-González; Angélica L. Sánchez-López; Lorenzo Sánchez-Romero; Eduardo I. Díaz-Barba; J. Francisco Santoscoy-Gutiérrez; Paloma Rivero-Moragrega
      Abstract: Publication date: Available online 7 March 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Genaro Gabriel Ortiz, Fermín P. Pacheco Moisés, Mario Mireles-Ramírez, Luis J. Flores-Alvarado, Héctor González-Usigli, Víctor J. Sánchez-González, Angélica L. Sánchez-López, Lorenzo Sánchez-Romero, Eduardo I. Díaz-Barba, J. Francisco Santoscoy-Gutiérrez, Paloma Rivero-Moragrega
      Molecular oxygen is essential for aerobic organisms in order to synthesize large amounts of energy during the process of oxidative phosphorylation and it is harnessed in the form of adenosine triphosphate, the chemical energy of the cell. Oxygen is toxic for anaerobic organisms but it is also less obvious that oxygen is poisonous to aerobic organisms at higher concentrations of oxygen. For instance, oxygen toxicity is a condition resulting from the harmful effects of breathing molecular oxygen at increased partial pressures. Reactive oxygen species (ROS) are chemically reactive molecules containing oxygen that are formed as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling and homeostasis. However, in pathological conditions ROS levels can increase dramatically. This may result in significant damage to cell structures. Living organisms have been adapted to the ROS in two ways: they can mitigate the unwanted effects through removal by the antioxidant systems and can advantageously use them as messengers in cell signaling and regulation of body functions. Some other physiological functions of ROS include the regulation of vascular tone, detection, and adaptation to hypoxia. In this review, we describe the mechanisms of oxidative damage and its relationship with the most highly studied neurodegenerative diseases.

      PubDate: 2017-03-09T16:01:25Z
      DOI: 10.1016/bs.apcsb.2017.01.003
       
  • Inflammation in Epileptic Encephalopathies
    • Authors: Oleksii Shandra; Solomon L. Moshé; Aristea S. Galanopoulou
      Abstract: Publication date: Available online 28 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Oleksii Shandra, Solomon L. Moshé, Aristea S. Galanopoulou
      West syndrome (WS) is an infantile epileptic encephalopathy that manifests with infantile spasms (IS), hypsarrhythmia (in ~60% of infants), and poor neurodevelopmental outcomes. The etiologies of WS can be structural–metabolic pathologies (~60%), genetic (12%–15%), or of unknown origin. The current treatment options include hormonal treatment (adrenocorticotropic hormone and high-dose steroids) and the GABA aminotransferase inhibitor vigabatrin, while ketogenic diet can be given as add-on treatment in refractory IS. There is a need to identify new therapeutic targets and more effective treatments for WS. Theories about the role of inflammatory pathways in the pathogenesis and treatment of WS have emerged, being supported by both clinical and preclinical data from animal models of WS. Ongoing advances in genetics have revealed numerous genes involved in the pathogenesis of WS, including genes directly or indirectly involved in inflammation. Inflammatory pathways also interact with other signaling pathways implicated in WS, such as the neuroendocrine pathway. Furthermore, seizures may also activate proinflammatory pathways raising the possibility that inflammation can be a consequence of seizures and epileptogenic processes. With this targeted review, we plan to discuss the evidence pro and against the following key questions. Does activation of inflammatory pathways in the brain cause epilepsy in WS and does it contribute to the associated comorbidities and progression? Can activation of certain inflammatory pathways be a compensatory or protective event? Are there interactions between inflammation and the neuroendocrine system that contribute to the pathogenesis of WS? Does activation of brain inflammatory signaling pathways contribute to the transition of WS to Lennox–Gastaut syndrome? Are there any lead candidates or unexplored targets for future therapy development for WS targeting inflammation?

      PubDate: 2017-03-03T12:44:54Z
      DOI: 10.1016/bs.apcsb.2017.01.005
       
  • Molecular Targets of Ascochlorin and Its Derivatives for Cancer Therapy
    • Authors: Jason Chua Min-Wen; Benjamin Chua Yan-Jiang; Srishti Mishra; Xiaoyun Dai; Junji Magae; Ng Shyh-Chang; Alan Prem Kumar; Gautam Sethi
      Abstract: Publication date: Available online 15 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Jason Chua Min-Wen, Benjamin Chua Yan-Jiang, Srishti Mishra, Xiaoyun Dai, Junji Magae, Ng Shyh-Chang, Alan Prem Kumar, Gautam Sethi
      Cancer is an extremely complex disease comprising of a multitude of characteristic hallmarks that continue to evolve with time. At the genomic level, random mutations leading to deregulation of diverse oncogenic signal transduction cascades and polymorphisms coupled with environmental as well as life style-related factors are major causative agent contributing to chemoresistance and the failure of conventional therapies as well as molecular targeted agents. Hence, there is an urgent need to identify novel alternative therapies based on alternative medicines to combat this dreaded disease. Ascochlorin (ASC), an isoprenoid antibiotic isolated initially from the fermented broth of Ascochyta viciae, and its synthetic derivatives have recently demonstrated substantial antineoplastic effects in a variety of tumor cell lines and mouse models. The major focus of this review article is to briefly analyze the chemopreventive as well as therapeutic properties of ASC and its derivatives and to identify the multiple molecular targets modulated by this novel class of anticancer agent.

      PubDate: 2017-02-17T07:31:15Z
      DOI: 10.1016/bs.apcsb.2017.01.001
       
  • Stress-Adaptive Response in Ovarian Cancer Drug Resistance: Role of TRAP1
           in Oxidative Metabolism-Driven Inflammation
    • Authors: Maria Rosaria Amoroso; Danilo Swann Matassa; Ilenia Agliarulo; Rosario Avolio; Francesca Maddalena; Valentina Condelli; Matteo Landriscina; Franca Esposito
      Abstract: Publication date: Available online 12 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Maria Rosaria Amoroso, Danilo Swann Matassa, Ilenia Agliarulo, Rosario Avolio, Francesca Maddalena, Valentina Condelli, Matteo Landriscina, Franca Esposito
      Metabolic reprogramming is one of the most frequent stress-adaptive response of cancer cells to survive environmental changes and meet increasing nutrient requirements during their growth. These modifications involve cellular bioenergetics and cross talk with surrounding microenvironment, in a dynamic network that connect different molecular processes, such as energy production, inflammatory response, and drug resistance. Even though the Warburg effect has long been considered the main metabolic feature of cancer cells, recent reports identify mitochondrial oxidative metabolism as a driving force for tumor growth in an increasing number of cellular contexts. In recent years, oxidative phosphorylation has been linked to a remodeling of inflammatory response due to autocrine or paracrine secretion of interleukines that, in turn, induces a regulation of gene expression involving, among others, molecules responsible for the onset of drug resistance. This process is especially relevant in ovarian cancer, characterized by low survival, high frequency of disease relapse and chemoresistance. Recently, the molecular chaperone TRAP1 (tumor necrosis factor-associated protein 1) has been identified as a key junction molecule in these processes in ovarian cancer: in fact, TRAP1 mediates a metabolic switch toward oxidative phosphorylation that, in turn, triggers cytokines secretion, with consequent gene expression remodeling, finally leading to cisplatin resistance and epithelial-to-mesenchymal transition in ovarian cancer models. This review summarizes how metabolism, chemoresistance, inflammation, and epithelial-to-mesenchymal transition are strictly interconnected, and how TRAP1 stays at the crossroads of these processes, thus shedding new lights on molecular networks at the basis of ovarian cancer.

      PubDate: 2017-02-17T07:31:15Z
      DOI: 10.1016/bs.apcsb.2017.01.004
       
  • Cardiokines as Modulators of Stress-Induced Cardiac Disorders
    • Authors: Anna Planavila; Joaquim Fernández-Solà; Francesc Villarroya
      Abstract: Publication date: Available online 10 February 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): Anna Planavila, Joaquim Fernández-Solà, Francesc Villarroya
      Almost 30 years ago, the protein, atrial natriuretic peptide, was identified as a heart-secreted hormone that provides a peripheral signal from the myocardium that communicates to the rest of the organism to modify blood pressure and volume under conditions of heart failure. Since then, additional peripheral factors secreted by the heart, termed cardiokines, have been identified and shown to coordinate this interorgan cross talk. In addition to this interorgan communication, cardiokines also act in an autocrine/paracrine manner to play a role in intercellular communication within the myocardium. This review focuses on the roles of newly emerging cardiokines that are mainly increased in stress-induced cardiac diseases. The potential of these cardiokines as clinical biomarkers for diagnosis and prognosis of cardiac disorders is also discussed.

      PubDate: 2017-02-11T02:26:12Z
      DOI: 10.1016/bs.apcsb.2017.01.002
       
  • Targeting IKK and NF-κB for Therapy
    • Authors: J.K. Durand; A.S. Baldwin
      Abstract: Publication date: Available online 11 January 2017
      Source:Advances in Protein Chemistry and Structural Biology
      Author(s): J.K. Durand, A.S. Baldwin
      In addition to regulating immune responses, the NF-κB family of transcription factors also promotes cellular proliferation and survival. NF-κB and its activating kinase, IKK, have become appealing therapeutic targets because of their critical roles in the progression of many diseases including chronic inflammation and cancer. Here, we discuss the conditions that lead to pathway activation, the effects of constitutive activation, and some of the strategies used to inhibit NF-κB signaling.

      PubDate: 2017-01-13T18:51:36Z
      DOI: 10.1016/bs.apcsb.2016.11.006
       
 
 
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