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Frontiers in Immunology 2021Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian... (Review)
Review
Protein S-palmitoylation is a covalent and reversible lipid modification that specifically targets cysteine residues within many eukaryotic proteins. In mammalian cells, the ubiquitous palmitoyltransferases (PATs) and serine hydrolases, including acyl protein thioesterases (APTs), catalyze the addition and removal of palmitate, respectively. The attachment of palmitoyl groups alters the membrane affinity of the substrate protein changing its subcellular localization, stability, and protein-protein interactions. Forty years of research has led to the understanding of the role of protein palmitoylation in significantly regulating protein function in a variety of biological processes. Recent global profiling of immune cells has identified a large body of S-palmitoylated immunity-associated proteins. Localization of many immune molecules to the cellular membrane is required for the proper activation of innate and adaptive immune signaling. Emerging evidence has unveiled the crucial roles that palmitoylation plays to immune function, especially in partitioning immune signaling proteins to the membrane as well as to lipid rafts. More importantly, aberrant PAT activity and fluctuations in palmitoylation levels are strongly correlated with human immunologic diseases, such as sensory incompetence or over-response to pathogens. Therefore, targeting palmitoylation is a novel therapeutic approach for treating human immunologic diseases. In this review, we discuss the role that palmitoylation plays in both immunity and immunologic diseases as well as the significant potential of targeting palmitoylation in disease treatment.
Topics: Acyltransferases; Adaptive Immunity; Animals; Humans; Immune System; Immune System Diseases; Immunity, Innate; Lipoylation; Protein Processing, Post-Translational; Proteins; Signal Transduction
PubMed: 34557182
DOI: 10.3389/fimmu.2021.661202 -
Biochimica Et Biophysica Acta.... Aug 2019Lipid homeostasis is critically dependent on the liver. Hepatic genes involved in lipid biosynthesis are controlled by combinatorial actions of multiple transcription... (Review)
Review
Lipid homeostasis is critically dependent on the liver. Hepatic genes involved in lipid biosynthesis are controlled by combinatorial actions of multiple transcription factors that include three sterol regulatory element binding proteins (SREBPs), carbohydrate responsive element binding protein, liver X receptors, and others. SREBP-1c, a seminal regulator of de novo lipogenesis, resides in the endoplasmic reticulum as a transcriptionally inert precursor and must undergo a regulated intramembrane proteolysis (RIP) prior to its nuclear translocation as a bone fide transcription factor. The regulation of biosynthesis, turnover and actions of SREBP-1c and lipogenesis are mechanistically linked to signaling kinases, canonically induced by macronutrients and insulin. Here, we briefly review the evidence showing that phosphorylation of SREBP-1c and its interacting partners, catalyzed by phosphatidyl inositol-3-kinase, protein kinase B, mechanistic target of rapamycin complex 1 and 2, mitogen activated protein kinases, glycogen synthase kinase-3β, protein kinase A and 5' adenosine monophosphate-activated protein kinase regulates the mechanisms of RIP and stability of SREBP-1c and de novo lipogenesis.
Topics: Animals; Humans; Lipogenesis; Phosphorylation; Proteostasis; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Proteins
PubMed: 31067497
DOI: 10.1016/j.bbalip.2019.04.015 -
Molecular Metabolism Aug 2020ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as... (Review)
Review
BACKGROUND
ATP-dependent chromatin remodelers are evolutionarily conserved complexes that alter nucleosome positioning to influence many DNA-templated processes, such as replication, repair, and transcription. In particular, chromatin remodeling can dynamically regulate gene expression by altering accessibility of chromatin to transcription factors.
SCOPE OF REVIEW
This review provides an overview of the importance of chromatin remodelers in the regulation of metabolic gene expression. Particular emphasis is placed on the INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers in both yeast and mammals. This review details discoveries from the initial identification of chromatin remodelers in Saccharomyces cerevisiae to recent discoveries in the metabolic requirements of developing embryonic tissues in mammals.
MAJOR CONCLUSIONS
INO80 and SWI/SNF (BAF/PBAF) chromatin remodelers regulate the expression of energy metabolism pathways in S. cerevisiae and mammals in response to diverse nutrient environments. In particular, the INO80 complex organizes the temporal expression of gene expression in the metabolically synchronized S. cerevisiae system. INO80-mediated chromatin remodeling is also needed to constrain cell division during metabolically favorable conditions. Conversely, the BAF/PBAF remodeler regulates tissue-specific glycolytic metabolism and is disrupted in cancers that are dependent on glycolysis for proliferation. The role of chromatin remodeling in metabolic gene expression is downstream of the metabolic signaling pathways, such as the TOR pathway, a critical regulator of metabolic homeostasis. Furthermore, the INO80 and BAF/PBAF chromatin remodelers have both been shown to regulate heart development, the tissues of which have unique requirements for energy metabolism during development. Collectively, these results demonstrate that chromatin remodelers communicate metabolic status to chromatin and are a central component of homeostasis pathways that optimize cell fitness, organismal development, and prevent disease.
Topics: Animals; Chromatin; Chromatin Assembly and Disassembly; DNA-Binding Proteins; Gene Expression; Gene Expression Regulation; Metabolic Networks and Pathways; Metabolism; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Transcription Factors; Transcriptional Activation
PubMed: 32251664
DOI: 10.1016/j.molmet.2020.100973 -
Current Drug Metabolism 2021Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of... (Review)
Review
BACKGROUND
Infections and inflammation lead to a downregulation of drug metabolism and kinetics in experimental animals. These changes in the expression and activities of drug-metabolizing enzymes may affect the effectiveness and safety of pharmacotherapy of infections and inflammatory conditions.
OBJECTIVE
In this review, we addressed the available evidence on the effects of malaria on drug metabolism activity and kinetics in rodents and humans.
RESULTS
An extensive literature review indicated that infection by Plasmodium spp consistently decreased the activity of hepatic Cytochrome P450s and phase-2 enzymes as well as the clearance of a variety of drugs in mice (lethal and non-lethal) and rat models of malaria. Malaria-induced CYP2A5 activity in the mouse liver was an exception. Except for paracetamol, pharmacokinetic trials in patients during acute malaria and in convalescence corroborated rodent findings. Trials showed that, in acute malaria, clearance of quinine, primaquine, caffeine, metoprolol, omeprazole, and antipyrine is slower and that AUCs are greater than in convalescent individuals.
CONCLUSION
Notwithstanding the differences between rodent models and human malaria, studies in P. falciparum and P. vivax patients confirmed rodent data showing that CYP-mediated clearance of antimalarials and other drugs is depressed during the symptomatic disease when rises in levels of acute-phase proteins and inflammatory cytokines occur. Evidence suggests that inflammatory cytokines and the interplay between malaria-activated NF-kB-signaling and cell pathways controlling phase 1/2 enzyme genes transcription mediate drug metabolism changes. The malaria-induced decrease in drug clearance may exacerbate drug-drug interactions, and the occurrence of adverse drug events, particularly when patients are treated with narrow-margin-of-safety medicines.
Topics: Animals; Antimalarials; Cytochrome P-450 Enzyme System; Drug Elimination Routes; Humans; Inactivation, Metabolic; Malaria; Metabolic Clearance Rate; Rodentia
PubMed: 33397251
DOI: 10.2174/1389200221999210101232057 -
Biomolecules Aug 2021Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely... (Review)
Review
Pregnane X Receptor (PXR) belongs to the nuclear receptors' superfamily and mainly functions as a xenobiotic sensor activated by a variety of ligands. PXR is widely expressed in normal and malignant tissues. Drug metabolizing enzymes and transporters are also under PXR's regulation. Antineoplastic agents are of particular interest since cancer patients are characterized by significant intra-variability to treatment response and severe toxicities. Various PXR polymorphisms may alter the function of the protein and are linked with significant effects on the pharmacokinetics of chemotherapeutic agents and clinical outcome variability. The purpose of this review is to summarize the roles of PXR polymorphisms in the metabolism and pharmacokinetics of chemotherapeutic drugs. It is also expected that this review will highlight the importance of PXR polymorphisms in selection of chemotherapy, prediction of adverse effects and personalized medicine.
Topics: Acetylation; Antineoplastic Agents; Biotransformation; Gene Expression; Humans; Inactivation, Metabolic; Neoplasms; Phosphorylation; Polymorphism, Single Nucleotide; Precision Medicine; Pregnane X Receptor; Protein Domains; Protein Processing, Post-Translational; Sumoylation; Treatment Outcome; Ubiquitination
PubMed: 34439808
DOI: 10.3390/biom11081142 -
International Journal of Cancer Nov 2023Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells...
Breast cancer is composed of metabolically coupled cellular compartments with upregulation of TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in carcinoma cells and loss of caveolin 1 (CAV1) with upregulation of monocarboxylate transporter 4 (MCT4) in fibroblasts. The mechanisms that drive metabolic coupling are poorly characterized. The effects of TIGAR on fibroblast CAV1 and MCT4 expression and breast cancer aggressiveness was studied using coculture and conditioned media systems and in-vivo. Also, the role of cytokines in promoting tumor metabolic coupling via MCT4 on cancer aggressiveness was studied. TIGAR downregulation in breast carcinoma cells reduces tumor growth. TIGAR overexpression in carcinoma cells drives MCT4 expression and NFkB activation in fibroblasts. IL6 and TGFB drive TIGAR upregulation in carcinoma cells, reduce CAV1 and increase MCT4 expression in fibroblasts. Tumor growth is abrogated in the presence of MCT4 knockout fibroblasts and environment. We discovered coregulation of c-MYC and TIGAR in carcinoma cells driven by lactate. Metabolic coupling primes the tumor microenvironment allowing for production, uptake and utilization of lactate. In sum, aggressive breast cancer is dependent on metabolic coupling.
Topics: Humans; Female; Breast Neoplasms; Apoptosis Regulatory Proteins; Glycolysis; Lactic Acid; NF-kappa B; Apoptosis; Carcinoma; Cell Line, Tumor; Tumor Microenvironment; Tumor Suppressor Protein p53
PubMed: 37497753
DOI: 10.1002/ijc.34660 -
Xenobiotica; the Fate of Foreign... May 2020Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and...
Metabolism and transport of many drugs oscillate with times of the day (solar time), resulting in circadian time-dependent drug exposure and pharmacokinetics.Time-dependent pharmacokinetics (also known as chronopharmacokinetics) is associated with time-varying drug effects and toxicity.This review summarizes drug-metabolizing enzymes and transporters with rhythmic expressions in the liver, intestine and/or kidney. Correlations of these diurnal proteins with circadian variations in drug exposure and effects/toxicity are covered. We also discuss the molecular mechanisms for circadian control of enzymes and transporters.Mechanism-based chronopharmacokinetics would facilitate a better understanding of chronopharmacology and the design of time-specific drug delivery systems, ultimately leading to improved drug efficacy and minimized toxicity.
Topics: Circadian Clocks; Circadian Rhythm; Drug Delivery Systems; Humans; Inactivation, Metabolic; Kidney; Liver; Membrane Transport Proteins; Metabolic Clearance Rate; Pharmaceutical Preparations
PubMed: 31544568
DOI: 10.1080/00498254.2019.1672120 -
Journal of Proteome Research Jan 2021Protein -acylation (commonly known as palmitoylation) is a widespread reversible lipid modification, which plays critical roles in regulating protein localization,... (Review)
Review
Protein -acylation (commonly known as palmitoylation) is a widespread reversible lipid modification, which plays critical roles in regulating protein localization, activity, stability, and complex formation. The deregulation of protein -acylation contributes to many diseases such as cancer and neurodegenerative disorders. The past decade has witnessed substantial progress in proteomic analysis of protein -acylation, which significantly advanced our understanding of -acylation biology. In this review, we summarized the techniques for the enrichment of -acylated proteins or peptides, critically reviewed proteomic studies of protein -acylation at eight different levels, and proposed major challenges for the -acylproteomics field. In summary, proteome-scale analysis of protein -acylation comes of age and will play increasingly important roles in discovering new disease mechanisms, biomarkers, and therapeutic targets.
Topics: Acylation; Lipoylation; Protein S; Proteome; Proteomics
PubMed: 33253586
DOI: 10.1021/acs.jproteome.0c00409 -
Journal of Proteome Research Jan 2020Redox proteomics is a field of proteomics that is concerned with the characterization of the oxidation state of proteins to gain information about their modulated... (Review)
Review
Redox proteomics is a field of proteomics that is concerned with the characterization of the oxidation state of proteins to gain information about their modulated structure, function, activity, and involvement in different physiological pathways. Oxidative modifications of proteins have been shown to be implicated in normal physiological processes of cells as well as in pathomechanisms leading to the development of cancer, diabetes, neurodegenerative diseases, and some rare hereditary metabolic diseases, like classic galactosemia. Reactive oxygen species generate a variety of reversible and irreversible modifications in amino acid residue side chains and within the protein backbone. These oxidative post-translational modifications (Ox-PTMs) can participate in the activation of signal transduction pathways and mediate the toxicity of harmful oxidants. Thus the application of advanced redox proteomics technologies is important for gaining insights into molecular mechanisms of diseases. Mass-spectrometry-based proteomics is one of the most powerful methods that can be used to give detailed qualitative and quantitative information on protein modifications and allows us to characterize redox proteomes associated with diseases. This Review illustrates the role and biological consequences of Ox-PTMs under basal and oxidative stress conditions by focusing on protein carbonylation and S-glutathionylation, two abundant modifications with an impact on cellular pathways that have been intensively studied during the past decade.
Topics: Humans; Oxidation-Reduction; Oxidative Stress; Protein Carbonylation; Protein Processing, Post-Translational; Proteome; Proteomics; Reactive Oxygen Species
PubMed: 31647248
DOI: 10.1021/acs.jproteome.9b00586 -
Drug Metabolism and Disposition: the... May 2020Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being... (Review)
Review
Dependence of drug metabolism on dosing time has long been recognized. However, only recently are the underlying mechanisms for circadian drug metabolism being clarified. Diurnal rhythmicity in expression of drug-metabolizing enzymes is believed to be a key factor determining circadian metabolism. Supporting the notion that biological rhythms are generated and maintained by the circadian clock, a number of diurnal enzymes are under the control of the circadian clock. In general, circadian clock genes generate and regulate diurnal rhythmicity in drug-metabolizing enzymes via transcriptional actions on one or two of three -elements (i.e., E-box, D-box, and Rev-erb response element or RAR-related orphan receptor response element). Additionally, cycling or clock-controlled nuclear receptors such as hepatocyte nuclear factor 4 and peroxisome proliferator-activated receptor are contributors to diurnal enzyme expression. These newly discovered mechanisms for each of the rhythmic enzymes are reviewed in this article. We also discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics. Our discussion is also extended to two diurnal transporters (P-glycoprotein and multidrug resistance-associated protein 2) that have an important role in drug absorption. Although the experimental evidence is lacking in metabolism-based chronoefficacy, circadian genes (e.g., ) as drug targets are shown to account for diurnal variability in drug efficacy. SIGNIFICANCE STATEMENT: Significant progress has been made in understanding the molecular mechanisms for generation of diurnal rhythmicity in drug-metabolizing enzymes. In this article, we review the newly discovered mechanisms for each of the rhythmic enzymes and discuss how the rhythms of enzymes are translated to circadian pharmacokinetics and drug chronotoxicity, which has direct implications for chronotherapeutics.
Topics: Animals; Circadian Clocks; Drug Chronotherapy; Humans; Metabolic Clearance Rate; Models, Animal; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Response Elements; Transcriptional Activation; Treatment Outcome
PubMed: 32114506
DOI: 10.1124/dmd.120.090472