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Trends in Biochemical Sciences Feb 2011Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic... (Review)
Review
Extensive studies during the past four decades have identified important roles for lysine acetylation in the regulation of nuclear transcription. Recent proteomic analyses on protein acetylation uncovered a large number of acetylated proteins in the cytoplasm and mitochondria, including most enzymes involved in intermediate metabolism. Acetylation regulates metabolic enzymes by multiple mechanisms, including via enzymatic activation or inhibition, and by influencing protein stability. Conversely, non-nuclear NAD(+)-dependent sirtuin deacetylases can regulate cellular and organismal metabolism, possibly through direct deacetylation of metabolic enzymes. Furthermore, acetylation of metabolic enzymes is highly conserved from prokaryotes to eukaryotes. Given the frequent occurrence of metabolic dysregulation in diabetes, obesity and cancer, enzymes modulating acetylation could provide attractive targets for therapeutic intervention for these diseases.
Topics: Acetylation; Animals; Humans; Metabolic Networks and Pathways; Protein Processing, Post-Translational; Proteins; Sirtuins
PubMed: 20934340
DOI: 10.1016/j.tibs.2010.09.003 -
Drug Metabolism and Disposition: the... Aug 2018Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome... (Review)
Review
Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA)-derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug-induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs.
Topics: Animals; Cardiotoxicity; Cardiovascular System; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Humans; Inactivation, Metabolic; Metabolic Clearance Rate; Xenobiotics
PubMed: 29695613
DOI: 10.1124/dmd.117.078964 -
Journal of Molecular and Cellular... Mar 2012Reversible protein S-glutathiolation has emerged as an important mechanism of post-translational modification. Under basal conditions several proteins remain adducted to... (Review)
Review
Reversible protein S-glutathiolation has emerged as an important mechanism of post-translational modification. Under basal conditions several proteins remain adducted to glutathione, and physiological glutathiolation of proteins has been shown to regulate protein function. Enzymes that promote glutathiolation (e.g., glutathione-S-transferase-P) or those that remove glutathione from proteins (e.g., glutaredoxin) have been identified. Modification by glutathione has been shown to affect protein catalysis, ligand binding, oligomerization and protein-protein interactions. Conditions associated with oxidative or nitrosative stress, such as ischemia-reperfusion, hypertension and tachycardia increase protein glutathiolation via changes in the glutathione redox status (GSH/GSSG) or through the formation of sulfenic acid (SOH) or nitrosated (SNO) cysteine intermediates. These "activated" thiols promote reversible S-glutathiolation of key proteins involved in cell signaling, energy production, ion transport, and cell death. Hence, S-glutathiolation is ideally suited for integrating and mounting fine-tuned responses to changes in the redox state. S-glutathiolation also provides a temporary glutathione "cap" to protect protein thiols from irreversible oxidation and it could be an important mechanism of protein "encryption" to maintain proteins in a functionally silent state until they are needed during conditions of stress. Current evidence suggests that the glutathiolation-deglutathiolation cycle integrates and interacts with other post-translational mechanisms to regulate signal transduction, metabolism, inflammation, and apoptosis. This article is part of a Special Section entitled "Post-translational Modification."
Topics: Animals; Glutathione; Glutathione Disulfide; Humans; Oxidation-Reduction; Oxidative Stress; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 21784079
DOI: 10.1016/j.yjmcc.2011.07.009 -
Drug Metabolism and Disposition: the... Jan 2014This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston,... (Review)
Review
This report summarizes a symposium sponsored by the American Society for Pharmacology and Experimental Therapeutics at Experimental Biology held April 20-24 in Boston, MA. Presentations discussed the status of cytochrome P450 (P450) knowledge, emphasizing advances and challenges in relating structure with function and in applying this information to drug design. First, at least one structure of most major human drug-metabolizing P450 enzymes is known. However, the flexibility of these active sites can limit the predictive value of one structure for other ligands. A second limitation is our coarse-grain understanding of P450 interactions with membranes, other P450 enzymes, NADPH-cytochrome P450 reductase, and cytochrome b5. Recent work has examined differential P450 interactions with reductase in mixed P450 systems and P450:P450 complexes in reconstituted systems and cells, suggesting another level of functional control. In addition, protein nuclear magnetic resonance is a new approach to probe these protein/protein interactions, identifying interacting b5 and P450 surfaces, showing that b5 and reductase binding are mutually exclusive, and demonstrating ligand modulation of CYP17A1/b5 interactions. One desired outcome is the application of such information to control drug metabolism and/or design selective P450 inhibitors. A final presentation highlighted development of a CYP3A4 inhibitor that slows clearance of human immunodeficiency virus drugs otherwise rapidly metabolized by CYP3A4. Although understanding P450 structure/function relationships is an ongoing challenge, translational advances will benefit from continued integration of existing and new biophysical approaches.
Topics: Cell Membrane; Cytochrome P-450 Enzyme System; Cytochromes b5; Humans; Inactivation, Metabolic; NADPH-Ferrihemoprotein Reductase; Protein Interaction Domains and Motifs
PubMed: 24130370
DOI: 10.1124/dmd.113.054627 -
Trends in Endocrinology and Metabolism:... Feb 2021β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate... (Review)
Review
β-Arrestin-1 and -2 are intracellular proteins that are able to inhibit signaling via G protein-coupled receptors (GPCRs). However, both proteins can also modulate cellular functions in a G protein-independent fashion. During the past few years, studies with mutant mice selectivity lacking β-arrestin-1 and/or -2 in metabolically important cell types have led to novel insights into the mechanisms through which β-arrestins regulate key metabolic processes in vivo, including whole-body glucose and energy homeostasis. The novel information gained from these studies should inform the development of novel drugs, including β-arrestin- or G protein-biased GPCR ligands, that could prove useful for the therapy of several important pathophysiological conditions, including type 2 diabetes and obesity.
Topics: Animals; Humans; Mice; Protein Binding; Receptors, G-Protein-Coupled; Signal Transduction; beta-Arrestins
PubMed: 33358450
DOI: 10.1016/j.tem.2020.11.008 -
Scientific Reports Apr 2017Mycothiol (MSH) is the major low molecular weight (LMW) thiol in Actinomycetes. Here, we used shotgun proteomics, OxICAT and RNA-seq transcriptomics to analyse protein...
Mycothiol (MSH) is the major low molecular weight (LMW) thiol in Actinomycetes. Here, we used shotgun proteomics, OxICAT and RNA-seq transcriptomics to analyse protein S-mycothiolation, reversible thiol-oxidations and their impact on gene expression in Mycobacterium smegmatis under hypochlorite stress. In total, 58 S-mycothiolated proteins were identified under NaOCl stress that are involved in energy metabolism, fatty acid and mycolic acid biosynthesis, protein translation, redox regulation and detoxification. Protein S-mycothiolation was accompanied by MSH depletion in the thiol-metabolome. Quantification of the redox state of 1098 Cys residues using OxICAT revealed that 381 Cys residues (33.6%) showed >10% increased oxidations under NaOCl stress, which overlapped with 40 S-mycothiolated Cys-peptides. The absence of MSH resulted in a higher basal oxidation level of 338 Cys residues (41.1%). The RseA and RshA anti-sigma factors and the Zur and NrdR repressors were identified as NaOCl-sensitive proteins and their oxidation resulted in an up-regulation of the SigH, SigE, Zur and NrdR regulons in the RNA-seq transcriptome. In conclusion, we show here that NaOCl stress causes widespread thiol-oxidation including protein S-mycothiolation resulting in induction of antioxidant defense mechanisms in M. smegmatis. Our results further reveal that MSH is important to maintain the reduced state of protein thiols.
Topics: Bacterial Proteins; Cysteine; Gene Expression Profiling; Glycopeptides; Hypochlorous Acid; Inositol; Metabolic Networks and Pathways; Metabolome; Mycobacterium smegmatis; Oxidants; Oxidation-Reduction; Protein Processing, Post-Translational; Proteome; Stress, Physiological
PubMed: 28446771
DOI: 10.1038/s41598-017-01179-4 -
Biochimica Et Biophysica Acta Sep 2016The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of... (Review)
Review
The so-called xenobiotic receptors (XRs) have functionally evolved into cellular sensors for both endogenous and exogenous stimuli by regulating the transcription of genes encoding drug-metabolizing enzymes and transporters, as well as those involving energy homeostasis, cell proliferation, and/or immune responses. Unlike prototypical steroid hormone receptors, XRs are activated through both direct ligand-binding and ligand-independent (indirect) mechanisms by a plethora of structurally unrelated chemicals. This review covers research literature that discusses direct vs. indirect activation of XRs. A particular focus is centered on the signaling control of the constitutive androstane receptor (CAR), the pregnane X receptor (PXR), and the aryl hydrocarbon receptor (AhR). We expect that this review will shed light on both the common and distinct mechanisms associated with activation of these three XRs. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie.
Topics: Animals; Constitutive Androstane Receptor; Energy Metabolism; Gene Expression Regulation; Heat-Shock Proteins; Humans; Inactivation, Metabolic; Intercellular Signaling Peptides and Proteins; Liver; Mitogen-Activated Protein Kinases; Phosphorylation; Pregnane X Receptor; Receptors, Aryl Hydrocarbon; Receptors, Cytoplasmic and Nuclear; Receptors, Steroid; Signal Transduction; Xenobiotics
PubMed: 26877237
DOI: 10.1016/j.bbagrm.2016.02.006 -
ACS Chemical Biology Jan 2023The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a...
The proteolysis targeting chimera (PROTAC) strategy results in the down-regulation of unwanted protein(s) for disease treatment. In the PROTAC process, a heterobifunctional degrader forms a ternary complex with a target protein of interest (POI) and an E3 ligase, which results in ubiquitination and proteasomal degradation of the POI. While ternary complex formation is a key attribute of PROTAC degraders, modification of the PROTAC molecule to optimize ternary complex formation and protein degradation can be a labor-intensive and tedious process. In this study, we take advantage of DNA-encoded library (DEL) technology to efficiently synthesize a vast number of possible PROTAC molecules and describe a parallel screening approach that utilizes DNA barcodes as reporters of ternary complex formation and cooperative binding. We use a designed PROTAC DEL against BRD4 and CRBN to describe a dual protein affinity selection method and the direct discovery of novel, potent BRD4 PROTACs that importantly demonstrate clear SAR. Such an approach evaluates all the potential PROTACs simultaneously, avoids the interference of PROTAC solubility and permeability, and uses POI and E3 ligase proteins in an efficient manner.
Topics: Nuclear Proteins; Transcription Factors; Ubiquitin-Protein Ligases; Ubiquitination; Proteolysis
PubMed: 36606710
DOI: 10.1021/acschembio.2c00797 -
Proteins Nov 2019The growing body of experimental and computational data describing how proteins interact with each other has emphasized the multiplicity of protein interactions and the...
The growing body of experimental and computational data describing how proteins interact with each other has emphasized the multiplicity of protein interactions and the complexity underlying protein surface usage and deformability. In this work, we propose new concepts and methods toward deciphering such complexity. We introduce the notion of interacting region to account for the multiple usage of a protein's surface residues by several partners and for the variability of protein interfaces coming from molecular flexibility. We predict interacting patches by crossing evolutionary, physicochemical and geometrical properties of the protein surface with information coming from complete cross-docking (CC-D) simulations. We show that our predictions match well interacting regions and that the different sources of information are complementary. We further propose an indicator of whether a protein has a few or many partners. Our prediction strategies are implemented in the dynJET algorithm and assessed on a new dataset of 262 protein on which we performed CC-D. The code and the data are available at: http://www.lcqb.upmc.fr/dynJET2/.
Topics: Algorithms; Animals; Binding Sites; Humans; Molecular Docking Simulation; Protein Binding; Protein Conformation; Protein Interaction Domains and Motifs; Protein Interaction Mapping; Protein Interaction Maps; Proteins; Software
PubMed: 31199528
DOI: 10.1002/prot.25757 -
Mitochondrion Jul 2020The biological function of plant mitochondrial uncoupling proteins (pUCPs) has been a matter of considerable controversy. For example, the pUCP capacity to uncouple... (Review)
Review
The biological function of plant mitochondrial uncoupling proteins (pUCPs) has been a matter of considerable controversy. For example, the pUCP capacity to uncouple respiration from ATP synthesis in vivo has never been fully acknowledged, in contrast to the mammalian UCP1 (mUCP1) role in uncoupling respiration-mediated thermogenesis. Interestingly, both pUCPs and mUCPs have been associated with stress response and metabolic perturbations. Some central questions that remain are how pUCPs and mUCPs compare in biochemical properties, molecular structure and cell biology under physiological and metabolically perturbed conditions. This review takes advantage of the large amount of data available for mUCPs to review the biochemical properties, 3D structure models and potential physiological roles of pUCPs during plant development and response to stress. The biochemical properties and structure of pUCPs are revisited in light of the recent findings that pUCPs catalyse the transport of metabolites across the mitochondrial inner membrane and the resolved mUCP2 protein structure. Additionally, transcriptional regulation and co-expression networks of UCP orthologues across species are analysed, taking advantage of publicly available curated experimental datasets. Taking these together, the biological roles of pUCPs are analysed in the context of their potential roles in thermogenesis, ROS production, cell signalling and the regulation of plant cellular bioenergetics. Finally, pUCPs biological function is discussed in the context of their potential role in protecting against environmental stresses.
Topics: Energy Metabolism; Gene Expression Regulation, Plant; Mitochondrial Uncoupling Proteins; Models, Molecular; Plant Development; Plant Proteins; Plants; Protein Conformation; Stress, Physiological
PubMed: 32439620
DOI: 10.1016/j.mito.2020.05.001