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Clinical Pharmacology and Therapeutics Apr 2011Transporters are membrane-bound proteins that control the access of endogenous and xenobiotics (drugs) to various sites in the human body. They influence drug...
Transporters are membrane-bound proteins that control the access of endogenous and xenobiotics (drugs) to various sites in the human body. They influence drug pharmacokinetics and pharmacodynamics (both benefit and risk) by affecting a drug's absorption, distribution, metabolism (via control of access to metabolizing enzymes), and excretion (ADME) and by controlling drug concentrations at the site of action. Like metabolizing enzymes, transporters have binding sites that are saturable and can be inhibited or induced.
Topics: Binding Sites; Biological Transport; Drug Interactions; Humans; Membrane Transport Proteins; Pharmacokinetics; Protein Binding; Tissue Distribution; Xenobiotics
PubMed: 21423238
DOI: 10.1038/clpt.2010.359 -
The Journal of Biological Chemistry Aug 2010Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous... (Review)
Review
Aerobic organisms are faced with a dilemma. Environmental iron is found primarily in the relatively inert Fe(III) form, whereas the more metabolically active ferrous form is a strong pro-oxidant. This conundrum is solved by the redox cycling of iron between Fe(III) and Fe(II) at every step in the iron metabolic pathway. As a transition metal ion, iron can be "metabolized" only by this redox cycling, which is catalyzed in aerobes by the coupled activities of ferric iron reductases (ferrireductases) and ferrous iron oxidases (ferroxidases).
Topics: Aerobiosis; Animals; Ceruloplasmin; FMN Reductase; Humans; Ion Transport; Iron; Oxidation-Reduction
PubMed: 20522542
DOI: 10.1074/jbc.R110.113217 -
Chemico-biological Interactions Nov 2016In plants, sulfur is an essential nutrient that must be converted into usable metabolic forms for the formation of sulfur-containing amino acids and peptides (primary... (Review)
Review
In plants, sulfur is an essential nutrient that must be converted into usable metabolic forms for the formation of sulfur-containing amino acids and peptides (primary route) and for the modification of diverse metabolites (secondary route). In plants, the fate of assimilated sulfate depends on the three enzymes - ATP sulfurylase, adenosine-5'-phosphate (APS) reductase, and APS kinase - that form a branchpoint in the pathway. ATP sulfurylase catalyzes the formation of the critical intermediate APS, which can either be used in the primary assimilatory route or be phosphorylated to 3'-phospho-APS (PAPS) for a variety of sulfation reactions. Recent biochemical and structural studies of the branchpoint enzymes in plant sulfur metabolism suggest that redox-regulation may control sulfur partitioning between primary and secondary routes. Disulfide-based redox switches differentially affect APS reductase and APS kinase. Oxidative conditions that promote disulfide formation increase the activity of APS reductase and decreases PAPS production by APS kinase. Here we review recent work on the ATP sulfurylase and APS kinase from plants that provide new insight on the regulation of PAPS formation, the structural evolution of these enzymes in different organisms, and redox-control of this key branchpoint in plant sulfur metabolism.
Topics: Metabolic Networks and Pathways; Oxidation-Reduction; Plant Proteins; Plants; Sulfates
PubMed: 26926807
DOI: 10.1016/j.cbi.2016.02.017 -
Molecular BioSystems Jan 2012We analyze human-specific KEGG pathways trying to understand the functional role of intrinsic disorder in proteins. Pathways provide a comprehensive picture of...
We analyze human-specific KEGG pathways trying to understand the functional role of intrinsic disorder in proteins. Pathways provide a comprehensive picture of biological processes and allow better understanding of a protein's function within the specific context of its surroundings. Our study pinpoints a few specific pathways significantly enriched in disorder-containing proteins and identifies the role of these proteins within the framework of pathway relationships. Three major categories of relations are shown to be significantly enriched in disordered proteins: gene expression, protein binding and to a lesser degree, protein phosphorylation. Finally we find that relations involving protein activation and to some extent inhibition are characterized by low disorder content.
Topics: Humans; Metabolic Networks and Pathways; Protein Binding; Protein Folding; Proteins
PubMed: 22012032
DOI: 10.1039/c1mb05274h -
American Journal of Physiology.... Dec 2017The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity...
The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol-fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion, and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1-mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or -acetyl cysteine (NAC; an antioxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted growth hormone-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity. Impaired growth hormone-mediated signaling is observed in ethanol-exposed hepatocytes and is explained by differential effects of alcohol dehydrogenase (ADH)- and cytochrome P 2E1 (CYP2E1)-mediated ethanol metabolism on the Jak2/STAT5B pathway.
Topics: Acetaldehyde; Acetylation; Alcohol Dehydrogenase; Animals; Antioxidants; Biotransformation; Cytochrome P-450 CYP2E1; Cytochrome P-450 CYP2E1 Inhibitors; Endocytosis; Ethanol; Growth Hormone; Hep G2 Cells; Humans; Janus Kinase 2; Liver; Microtubule Proteins; Oxidative Stress; Protein Processing, Post-Translational; Protein Transport; Rats; Reactive Oxygen Species; STAT5 Transcription Factor; Signal Transduction
PubMed: 28864499
DOI: 10.1152/ajpgi.00027.2017 -
Critical Reviews in Biochemistry and... 2015Eukaryotic organisms use diverse mechanisms to control metabolic rates in response to changes in the internal and/or external environment. Fine metabolic control is a... (Review)
Review
Eukaryotic organisms use diverse mechanisms to control metabolic rates in response to changes in the internal and/or external environment. Fine metabolic control is a highly responsive, energy-saving process that is mediated by allosteric inhibition/activation and/or reversible modification of preexisting metabolic enzymes. In contrast, coarse metabolic control is a relatively long-term and expensive process that involves modulating the level of metabolic enzymes. Coarse metabolic control can be achieved through the degradation of metabolic enzymes by the ubiquitin-proteasome system (UPS), in which substrates are specifically ubiquitinated by an E3 ubiquitin ligase and targeted for proteasomal degradation. Here, we review select multi-protein E3 ligase complexes that directly regulate metabolic enzymes in Saccharomyces cerevisiae. The first part of the review focuses on the endoplasmic reticulum (ER) membrane-associated Hrd1 and Doa10 E3 ligase complexes. In addition to their primary roles in the ER-associated degradation pathway that eliminates misfolded proteins, recent quantitative proteomic analyses identified native substrates of Hrd1 and Doa10 in the sterol synthesis pathway. The second part focuses on the SCF (Skp1-Cul1-F-box protein) complex, an abundant prototypical multi-protein E3 ligase complex. While the best-known roles of the SCF complex are in the regulation of the cell cycle and transcription, accumulating evidence indicates that the SCF complex also modulates carbon metabolism pathways. The increasing number of metabolic enzymes whose stability is directly regulated by the UPS underscores the importance of the proteolytic regulation of metabolic processes for the acclimation of cells to environmental changes.
Topics: Endoplasmic Reticulum-Associated Degradation; F-Box Proteins; Metabolic Networks and Pathways; Proteolysis; SKP Cullin F-Box Protein Ligases; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Ubiquitin-Protein Ligases
PubMed: 26362128
DOI: 10.3109/10409238.2015.1081869 -
Journal of Lipid Research Feb 2011Protein S-acylation is a major posttranslational modification whereby a cysteine thiol is converted to a thioester. A prototype is S-palmitoylation (fatty acylation), in...
Protein S-acylation is a major posttranslational modification whereby a cysteine thiol is converted to a thioester. A prototype is S-palmitoylation (fatty acylation), in which a protein undergoes acylation with a hydrophobic 16 carbon lipid chain. Although this modification is a well-recognized determinant of protein function and localization, current techniques to study cellular S-acylation are cumbersome and/or technically demanding. We recently described a simple and robust methodology to rapidly identify S-nitrosylation sites in proteins via resin-assisted capture (RAC) and provided an initial description of the applicability of the technique to S-acylated proteins (acyl-RAC). Here we expand on the acyl-RAC assay, coupled with mass spectrometry-based proteomics, to characterize both previously reported and novel sites of endogenous S-acylation. Acyl-RAC should therefore find general applicability in studies of both global and individual protein S-acylation in mammalian cells.
Topics: Acylation; Cysteine; Electrophoresis, Polyacrylamide Gel; Lipoylation; Protein Processing, Post-Translational; Proteins; Sepharose; ras Proteins
PubMed: 21044946
DOI: 10.1194/jlr.D011106 -
European Journal of Drug Metabolism and... Oct 2017Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents... (Review)
Review
Genetic variability in drug-metabolizing enzymes and drug transporters is known to influence the pharmacokinetics of many drugs. Antimalarial drugs are a class of agents known to utilize metabolic and elimination pathways prone to genetic variation. This paper aims to review the genetic variants affecting antimalarial medications and discuss their clinical implications. Data were identified for the genes coding for the cytochrome P450 (CYP) enzymes: CYP2C8, CYP2C19, CYP2A6, CYP2D6, CYP2B6, and the P-glycoprotein drug transporter. Adverse effects of amodiaquine were more common in patients with decreased CYP2C8 metabolism. CYP2C19 variants influenced the metabolism of proguanil but no differences in efficacy outcomes were observed. Ultra-metabolizers of CYP2A6 showed increased incidence of adverse effects of artesunate (prodrug for active metabolite, dihydroartemisinin). In the presence of efavirenz, mutations in CYP2B6 influenced the number of patients achieving day-7 lumefantrine concentrations above accepted therapeutic cut-offs. Lumefantrine concentrations were also influenced by ABCB1 variants in the presence of nevirapine. The most critical pharmacogenetic consideration identified was the association of glucose-6-phosphate dehydrogenase deficiency with development of hemolytic anemia and decreased hemoglobin levels in patients treated with primaquine or a combination of chlorproguanil-dapsone-artesunate. These findings demonstrate a need for close monitoring of patients originating from populations where genetic variation in metabolizing enzymes is prevalent, so as to ensure that optimal clinical outcomes are achieved. Future studies should determine which populations are at greatest risk of potential treatment failures and/or adverse effects, which drugs are most susceptible to genetic variation in metabolizing enzymes, and the impact of genetic influence on the efficacy and safety of first-line treatment regimens.
Topics: Animals; Antimalarials; Genetic Variation; Humans; Inactivation, Metabolic; Malaria; Membrane Transport Proteins; Pharmacogenetics
PubMed: 28070879
DOI: 10.1007/s13318-016-0399-1 -
Journal of Biosciences Sep 2016Copper, although known as a micronutrient, has a pivotal role in modulating the cellular metabolism. Many studies have reported the role of copper in angiogenesis.... (Review)
Review
Copper, although known as a micronutrient, has a pivotal role in modulating the cellular metabolism. Many studies have reported the role of copper in angiogenesis. Copper chaperones are intracellular proteins that mediate copper trafficking to various cell organelles. However, the role and function of copper chaperones in relation to angiogenesis has to be further explored. The intracellular copper levels when in excess are deleterious and certain mutations of copper chaperones have been shown to induce cell death and influence various cellular metabolisms. The study of these chaperones will be helpful in understanding the players in the cascade of events in angiogenesis and their role in cellular metabolic pathways. In this review we have briefly listed the copper chaperones associated with angiogenic and metabolic signalling and their function.
Topics: Copper; Humans; Ion Transport; Metabolic Networks and Pathways; Molecular Chaperones; Neovascularization, Physiologic
PubMed: 27581939
DOI: 10.1007/s12038-016-9629-6 -
Seminars in Cell Biology Apr 1995Five cyclin-like genes, cig1, cig2/cyc17, mcs2, puc1 and cdc13, have been discovered in S. pombe to date. It is not yet clear what their functions are or even whether... (Comparative Study)
Comparative Study Review
Five cyclin-like genes, cig1, cig2/cyc17, mcs2, puc1 and cdc13, have been discovered in S. pombe to date. It is not yet clear what their functions are or even whether they are all involved with control of the cell cycle. Conflicting data for cig1 and cig2/cyc17 have obscured analysis of their function and cig1 remains largely uncharacterized, although clues to the role of cig2/cyc17 have emerged. There is genetic data available for the more distant cyclin homologue mcs2, which has an essential although as yet unspecified role. Puc1 may be involved in regulation of exit from the cell cycle. The first cyclin to be discovered, and the best understood, is cdc13 which with cdc2 promotes mitosis. Studies of the roles of cdc2 and cdc13 in the overall ordering of the cell cycle suggest that cdc13 and probably other cyclins are key regulators, maintaining the order of S phase and mitosis during the cell cycle.
Topics: Cell Cycle; Cell Cycle Proteins; Cloning, Molecular; Cyclin B; Cyclins; Fungal Proteins; G1 Phase; Genes, Fungal; Humans; Phosphorylation; Protein Processing, Post-Translational; Schizosaccharomyces; Schizosaccharomyces pombe Proteins; Sequence Homology
PubMed: 7548845
DOI: 10.1016/1043-4682(95)90003-9