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Nucleic Acids Research Jan 2021Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major...
Drug-metabolizing enzymes (DMEs) are critical determinant of drug safety and efficacy, and the interactome of DMEs has attracted extensive attention. There are 3 major interaction types in an interactome: microbiome-DME interaction (MICBIO), xenobiotics-DME interaction (XEOTIC) and host protein-DME interaction (HOSPPI). The interaction data of each type are essential for drug metabolism, and the collective consideration of multiple types has implication for the future practice of precision medicine. However, no database was designed to systematically provide the data of all types of DME interactions. Here, a database of the Interactome of Drug-Metabolizing Enzymes (INTEDE) was therefore constructed to offer these interaction data. First, 1047 unique DMEs (448 host and 599 microbial) were confirmed, for the first time, using their metabolizing drugs. Second, for these newly confirmed DMEs, all types of their interactions (3359 MICBIOs between 225 microbial species and 185 DMEs; 47 778 XEOTICs between 4150 xenobiotics and 501 DMEs; 7849 HOSPPIs between 565 human proteins and 566 DMEs) were comprehensively collected and then provided, which enabled the crosstalk analysis among multiple types. Because of the huge amount of accumulated data, the INTEDE made it possible to generalize key features for revealing disease etiology and optimizing clinical treatment. INTEDE is freely accessible at: https://idrblab.org/intede/.
Topics: Bacteria; DNA Methylation; Databases, Factual; Drugs, Investigational; Enzymes; Fungi; Histones; Humans; Inactivation, Metabolic; Internet; Metabolic Clearance Rate; Microbiota; Prescription Drugs; Protein Processing, Post-Translational; RNA, Long Noncoding; Software; Xenobiotics
PubMed: 33045737
DOI: 10.1093/nar/gkaa755 -
Nutrition (Burbank, Los Angeles County,... 1995A large number of "biologic markers" for cancer have been described, including tumor-associated antigens, ectopic hormones, enzymes, and effects of tumor on the host's... (Review)
Review
A large number of "biologic markers" for cancer have been described, including tumor-associated antigens, ectopic hormones, enzymes, and effects of tumor on the host's metabolism. Although tumors may metabolically differ from each other, they may induce similar derangements in glucose, lipid, and protein metabolism in the host. In particular, changes in carbohydrate metabolism may induce glucose intolerance that may be early and easily detected using an oral glucose tolerance test. Hypertriglyceridemia and reduced exogenous lipid clearance may represent an early marker of deranged lipid metabolism. Changes in protein metabolism, as reflected by plasma amino acid profile, may also represent a new diagnostic tool for cancer. Among other amino acids, free tryptophan seems to be the best candidate as a new useful marker for monitoring neoplastic disease. It is conceivable that, based on the understanding of the differences in plasma amino acid profiles, more specific and rational antineoplastic strategies may arise.
Topics: Biomarkers, Tumor; Carbohydrate Metabolism; Humans; Lipid Metabolism; Neoplasms; Proteins
PubMed: 8748231
DOI: No ID Found -
Pharmacology & Therapeutics Jan 2006Renal failure not only alters the renal elimination, but also the non-renal disposition of drugs that are extensively metabolized by the liver. Although reduced... (Review)
Review
Renal failure not only alters the renal elimination, but also the non-renal disposition of drugs that are extensively metabolized by the liver. Although reduced metabolic enzyme activity in some cases can be responsible for the reduced drug clearance, alterations in the transporter systems may also be involved in the process. With the development of renal failure, the renal secretion of organic ions mediated by organic anion transporters (OATs) and organic cation transporters (OCTs) is decreased. 3-Carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) and other organic anionic uremic toxins may directly inhibit the renal excretion of various drugs and endogenous organic acids by competitively inhibiting OATs. In addition, the expression of OAT1 and OCT2 was reduced in chronic renal failure (CRF) rats. Renal failure also impairs the liver uptake of drugs and organic anions, such as bromosulphophthalein (BSP), indocyanine green (ICG), and thyroxine, where organic anion transport polypeptides (OATPs) are the major transporters. Most previous studies have been done in animals or cell culture, very often in rat models, but these are presumed to reflect the presentation of advanced renal disease in humans as well. Recent studies demonstrate that the uremic toxins CMPF and indoxyl sulfate (IS) can directly inhibit rOatp2 and hOATP-C in hepatocytes. The protein content of the liver uptake transporters Oatp1, 2, and 4 were significantly decreased in CRF rats. Decreased activity of the intestinal efflux transporter, P-glycoprotein (P-gp), was also observed in CRF rats, with no significant change of protein content, suggesting that uremic toxins may suppress P-gp function. However, increased protein levels of multidrug resistance-associated protein (MRP) 2 in the kidney and MRP3 in the liver were found in CRF rats, suggesting an adaptive response that may serve as a protective mechanism. Increases in drug areas under the curve (AUCs) in subjects with advanced renal disease for drugs that are not renally excreted are consistent with uremic toxin effects on either intestinal or hepatic cell transporters, metabolizing enzymes, or both. In conclusion, alterations of drug transporters, as well as metabolic enzymes, in patients with renal failure can be responsible for reduced drug clearance.
Topics: Animals; Biological Transport, Active; Carrier Proteins; Humans; Liver; Multidrug Resistance-Associated Protein 2; Pharmaceutical Preparations; Renal Insufficiency
PubMed: 16085315
DOI: 10.1016/j.pharmthera.2005.05.010 -
Free Radical Research May 2005Cell signaling entails a host of post-translational modifications of effector-proteins. These modifications control signal transmission by regulating the activity,... (Review)
Review
Post-translational disulfide modifications in cell signaling--role of inter-protein, intra-protein, S-glutathionyl, and S-cysteaminyl disulfide modifications in signal transmission.
Cell signaling entails a host of post-translational modifications of effector-proteins. These modifications control signal transmission by regulating the activity, localization or half-life of the effector-protein. Prominent oxidative modifications induced by cell-signaling reactive oxygen species (ROS) are cysteinyl modifications such as S-nitrosylation, sulfenic acid and disulfide formation. Disulfides protect protein sulfhydryls against oxidative destruction and simultaneously influence cell signaling by engaging redox-regulatory sulfhydryls in effector-proteins. The types of disulfides implicated in signaling span (1) protein S-glutathionylation, e.g. as a novel mode of Ras activation through S-glutathionylation at Cys-118 in response to a hydrogen-peroxide burst, (2) intra-protein disulfides, e.g. in the regulation of the stability of the protein phosphatase Cdc25C by hydrogen-peroxide, (3) inter-protein disulfides, e.g. in the hydrogen peroxide-mediated inactivation of receptor protein-tyrosine phosphatase alpha (RPTPalpha) by dimerization and (4) protein S-cysteaminylation by cystamine. Cystamine is a byproduct of pantetheinase-catalyzed pantothenic acid recycling from pantetheine for biosynthesis of Coenzyme A (CoA), a ubiquitous and metabolically indispensable cofactor. Cystamine inactivates protein kinase C-epsilon (PKCepsilon), gamma-glutamylcysteine synthetase and tissue transglutaminase by S-cysteaminylation-triggered mechanisms. The importance of protein S-cysteaminylation in signal transmission in vivo is evident from the ability of cystamine administration to rescue the intestinal inflammatory-response deficit of pantetheinase knockout mice. These mice lack the predominant epithelial pantetheinase isoform and have sharply reduced levels of cystamine/cysteamine in epithelial tissues. In addition, intraperitoneal administration of cystamine significantly delays neurodegenerative pathogenesis in a Huntington's disease mouse model. Thus, cystamine may serve as a prototype for the development of novel therapeutics that target effector-proteins regulated by S-cysteaminylation.
Topics: Animals; Cystamine; Disulfides; Glutathione; Humans; Huntington Disease; Mice; Oxidation-Reduction; Protein Processing, Post-Translational; Proteins; Reactive Oxygen Species; Signal Transduction
PubMed: 16036322
DOI: 10.1080/10715760500073931 -
Toxicology and Applied Pharmacology Sep 2005The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human... (Review)
Review
The cytochrome P450 enzymes are highly expressed in the liver and are involved in the metabolism of xenobiotics. Because of the initiatives associated with the Human Genome Project, a great progress has recently been seen in the identification and characterization of novel extrahepatic P450s, including CYP2S1, CYP2R1, CYP2U1 and CYP2W1. Like the hepatic enzymes, these P450s may play a role in the tissue-specific metabolism of foreign compounds, but they may also have important endogenous functions. CYP2S1 has been shown to metabolize all-trans retinoic acid and CYP2R1 is a major vitamin D 25-hydroxylase. Regarding their metabolism of xenobiotics, much remains to be established, but CYP2S1 metabolizes naphthalene and it is likely that these P450s are responsible for metabolic activation of several different kinds of xenobiotic chemicals and contribute to extrahepatic toxicity and carcinogenesis.
Topics: Animals; Biotransformation; Cytochrome P-450 Enzyme System; Humans; Liver; Xenobiotics
PubMed: 15987645
DOI: 10.1016/j.taap.2004.12.022 -
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 -
Biochimica Et Biophysica Acta Jun 2007A central principle of signal transduction is the appropriate control of the process so that relevant signals can be detected with fine spatial and temporal resolution.... (Review)
Review
A central principle of signal transduction is the appropriate control of the process so that relevant signals can be detected with fine spatial and temporal resolution. In the case of lipid-mediated signaling, organization and metabolism of specific lipid mediators is an important aspect of such control. Herein, we review the emerging evidence regarding the roles of Sec14-like phosphatidylinositol transfer proteins (PITPs) in the action of intracellular signaling networks; particularly as these relate to membrane trafficking. Finally, we explore developing ideas regarding how Sec14-like PITPs execute biological function. As Sec14-like proteins define a protein superfamily with diverse lipid (or lipophile) binding capabilities, it is likely these under-investigated proteins will be ultimately demonstrated as a ubiquitously important set of biological regulators whose functions influence a large territory in the signaling landscape of eukaryotic cells.
Topics: Animals; Biological Transport; Carrier Proteins; Crystallization; Humans; Membrane Lipids; Metabolic Networks and Pathways; Models, Molecular; Phosphatidylcholines; Phosphatidylinositols; Phospholipid Transfer Proteins; Phospholipids; Protein Binding; Saccharomyces cerevisiae Proteins; Signal Transduction
PubMed: 17512778
DOI: 10.1016/j.bbalip.2007.04.002 -
Journal of Lipid Research Jul 2006Much is now understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic... (Review)
Review
Much is now understood concerning the synthesis of prenylated and palmitoylated proteins, but what is known of their metabolic fate? This review details metabolic pathways for the lysosomal degradation of S-fatty acylated and prenylated proteins. Central to these pathways are two lysosomal enzymes, palmitoyl-protein thioesterase (PPT1) and prenylcysteine lyase (PCL). PPT1 is a soluble lipase that cleaves fatty acids from cysteine residues in proteins during lysosomal protein degradation. Notably, deficiency in the enzyme causes a neurodegenerative lysosomal storage disorder, infantile neuronal ceroid lipofuscinosis. PCL is a membrane-associated flavin-containing lysosomal monooxygenase that metabolizes prenylcysteine to prenyl aldehyde through a completely novel mechanism. The eventual metabolic fates of other lipidated proteins (such as glycosylphosphatidylinositol-anchored and N-myristoylated proteins) are poorly understood, suggesting directions for future research.
Topics: Animals; Carbon-Sulfur Lyases; Glycosylphosphatidylinositols; Humans; Lipid Metabolism; Lysosomes; Models, Molecular; Mutation; Myristic Acids; Protein Prenylation; Protein Processing, Post-Translational; Proteins; Thiolester Hydrolases
PubMed: 16627894
DOI: 10.1194/jlr.R600010-JLR200 -
Trends in Microbiology Jan 2004The yiaQRS genes of Escherichia coli K-12 are involved in carbohydrate metabolism. Clustering of homologous genes was found throughout several unrelated bacteria.... (Review)
Review
The yiaQRS genes of Escherichia coli K-12 are involved in carbohydrate metabolism. Clustering of homologous genes was found throughout several unrelated bacteria. Strikingly, all four bacterial transport protein classes were found, conserving transport function but not mechanism. It appears that during evolution the ability to transport, phosphorylate and metabolize substrates of unknown identity have been conserved. However, the transporter classes have been swapped. This probably demonstrates the subtlety of transport-protein evolution.
Topics: Bacteria; Bacterial Proteins; Biological Transport; Carbohydrate Metabolism; Evolution, Molecular; Membrane Transport Proteins; Multigene Family
PubMed: 14700544
DOI: 10.1016/j.tim.2003.11.001 -
Biochemistry and Cell Biology =... 2001The movement of lipids from their sites of synthesis to ultimate intracellular destinations must be coordinated with lipid metabolic pathways to ensure overall lipid... (Review)
Review
The movement of lipids from their sites of synthesis to ultimate intracellular destinations must be coordinated with lipid metabolic pathways to ensure overall lipid homeostasis is maintained. Thus, lipids would be predicted to play regulatory roles in the movement of vesicles within cells. Recent work has highlighted how specific lipid metabolic events can affect distinct vesicle trafficking steps and has resulted in our first glimpses of how alterations in lipid metabolism participate in the regulation of intracellular vesicles. Specifically, (i) alterations in sphingolipid metabolism affect the ability of SNAREs to fuse membranes, (ii) sterols are required for efficient endocytosis, (iii) glycerophospholipids and phosphorylated phosphatidylinositols regulate Golgi-mediated vesicle transport, (iv) lipid acylation is required for efficient vesicle transport mediated membrane fission, and (v) the addition of glycosylphosphatidylinositol lipid anchors to proteins orders them into distinct domains that result in their preferential sorting from other vesicle destined protein components in the endoplasmic reticulum. This review describes the experimental evidence that demonstrates a role for lipid metabolism in the regulation of specific vesicle transport events.
Topics: Acylation; Acyltransferases; Biological Transport; Carrier Proteins; Cytoplasmic Vesicles; Glycerophospholipids; Glycosylphosphatidylinositols; Lipid Metabolism; Membrane Proteins; Phosphatidylcholines; Phosphatidylinositols; Phospholipid Transfer Proteins; Phosphorylation; SNARE Proteins; Saccharomyces cerevisiae Proteins; Sphingolipids; Sterols; Vesicular Transport Proteins
PubMed: 11800009
DOI: 10.1139/o01-139