Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.1.1.67 (thiopurine methyltransferase)
551 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Methyl conjugation is an important pathway in the biotransformation of many drugs and xenobiotic compounds. 'Pharmacogenetic' variation exists in the activities of many methyltransferase enzymes, and experiments with the drug-metabolizing enzyme thiopurine methyltransferase (TPMT) offer a model for one approach that has proven useful in the study of methyltransferase pharmacogenetics. 2. TPMT catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. This enzyme activity is present in the human red blood cell (RBC), and RBC TPMT activity is controlled by a common genetic polymorphism that regulates also the enzyme activity in all other human tissues that have been studied. 3. Subjects with inherited low levels of TPMT activity are at increased risk for thiopurine drug-induced myelotoxicity, while patients with high TPMT activities may be 'undertreated' with these drugs. 4. TPMT activity in tissue from selected strains of inbred mice also is regulated by a genetic polymorphism. These mice provide an animal model for use in the study of pharmacological or toxicological consequences of inherited differences in TPMT activity. 4. Other methyltransferase enzymes including thiol methyltransferase, catechol O-methyltransferase, and histamine N-methyltransferase also are present in the human RBC, are regulated by inheritance, and are responsible for individual variation in drug metabolism. Enhanced understanding of the pharmacogenetics of methylation may make it possible to understand and predict individual variation in the biotransformation, toxicity and therapeutic effect of compounds that undergo methyl conjugation.
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PMID:Methylation pharmacogenetics: thiopurine methyltransferase as a model system. 144 97

Rat liver cytosolic thiopurine methyltransferase and microsomal thiol methyltransferase were each found to be subject to control by the absolute molar ratio of S-adenosylmethionine to S-adenosylhomocysteine using cell-free enzyme preparations. As this ratio was lowered, inhibition of both sulfhydryl xenobiotic transmethylases occurred. On the other hand, when the ratio was decreased in vivo by the administration of D,L-homocysteine thiolactone to animals, this alteration was accompanied by an inhibition of only thiopurine methyltransferase activity. Thiol methyltransferase activity was not significantly affected after drug treatment, which would suggest that there is a compartmentalization of S-adenosylhomocysteine in the intact hepatocyte.
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PMID:Effect of S-adenosylhomocysteine on sulfhydryl xenobiotic transmethylases in rat liver. 399 29

Methyl conjugation is an important pathway in drug metabolism. Activities of three human drug-metabolizing methyltransferase enzymes, catechol-O-methyltransferase (COMT) (EC 2.1.1.6), thiopurine methyltransferase ( TPMT ) (EC 2.1.1.67), and thiol methyltransferase (TMT) (EC 2.1.1.9), are controlled by inheritance. COMT activity in the red blood cell (RBC) is regulated by a single genetic locus with two alleles, COMTL for low activity and COMTH for high activity. Gene frequencies of these two alleles were approximately equal in a white population sample of Northern European origin. The genetically controlled level of COMT activity in the RBC reflects the level of enzyme activity in other tissues and is significantly correlated with individual variations in the methyl conjugation of catechol drugs such as L-dopa and methyldopa. TPMT catalyzes the S-methylation of thiopurines and thiopyrimidines . RBC TPMT activity is also controlled by a single genetic locus with two alleles, TPMTL for low and TPMTH for high activity. The gene frequencies of these two alleles were 0.06 and 0.94, respectively, in a white population sample. RBC TPMT activity reflects the level of enzyme activity in other cells and tissues such as the lymphocyte and kidney. TMT catalyzes the S-methylation of aliphatic sulfhydryl compounds such as the drugs captopril and D-penicillamine. The heritability of the level of RBC membrane TMT activity has been estimated on the basis of family studies to be approximately 0.98. Regulation of these three methyl-conjugating enzymes by inheritance raises the possibility that genetically determined methylator status may be one factor responsible for variations in drug metabolism in humans.
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PMID:Human pharmacogenetics of methyl conjugation. 671 37

1. The activities of the microsomal thiol methyltransferase and the cytosolic thiopurine methyltransferase were measured with 2-mercaptoethanol and 6-mercaptopurine as substrates in human ileum, ascending colon, transverse colon, descending colon and liver. 2. Thiol methyltransferase activity (pmol/min per mg) (mean +/- SD) was 495 +/- 280 (ileum), 786 +/- 454 (ascending colon), 1791 +/- 233 (transverse colon), 964 +/- 484 (descending colon) and 4800 +/- 1194 (liver). 3. Thiopurine methyltransferase (pmol/min per mg) (mean +/- SD) was 53.5 +/- 15.4 (ileum), 34.6 +/- 11.4 (ascending colon), 64.3 +/- 12.1 (transverse colon), 57.0 +/- 10.1 (descending colon) and 106 +/- 20.4 (liver). 4. Transferase in intestinal mucosa followed non-Michaelis-Menten kinetics, and two phases representing high and low affinity forms, for the acceptor methyl substrates were observed. 5. Comparison of intestinal with hepatic activities showed that thiopurine methyltransferase is better expressed than thiol methyltransferase in the human intestine, at least with the substrates studied.
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PMID:S-methyltransferases in human intestine: differential distribution of the microsomal thiol methyltransferase and cytosolic thiopurine methyltransferase along the human bowel. 821 40

Thiopurine S-methyltransferase is a cytosolic enzyme that catalyzes the S-methylation of thiopurine drugs. Although a genetic polymorphism has been recognized for this enzyme in populations of Caucasian descent, there has been scanty information about this polymorphism among Asians. In this study, we measured the erythrocyte thiopurine methyltransferase activity in 119 healthy Chinese subjects by a radiochemical assay. Methyltransferase activity was lower than what might have been expected for a white population. A bimodal frequency distribution was obtained that allowed the identification of four individuals with relatively low methyltransferase activity who may be heterozygotes for thiopurine S-methyltransferase deficiency; if so, the frequency of the mutant allele would be lower in this Chinese population than that observed in a white population (chi 2, p < 0.02). No gender-based differences were observed.
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PMID:Thiopurine S-methyltransferase activity in a Chinese population. 833 Apr 62

Disulfiram is used in the treatment of alcoholism to inhibit the enzyme aldehyde dehydrogenase. Disulfiram is rapidly reduced in vivo to form diethyldithiocarbamate (DDC), and DDC can undergo methyl conjugation to form S-methyl-DDC. Human tissues contain two separate genetically regulated enzymes that can catalyze thiol S-methylation. Thiol methyltransferase (TMT) is a microsomal enzyme that preferentially catalyzes, the S-methylation of alipathic sulfhydryl compounds, whereas thiopurine methyltransferase (TPMT) is a cytoplasmic enzyme that preferentially catalyzes the S-methylation of aromatic and heterocyclic sulfhydryl compounds. Our experiments were performed to determine whether human liver microsomal and/or cytosolic preparations could catalyze the S-methylation of DDC, and, if so, to determine whether TMT or TPMT might be the enzymes involved. We found that both human liver microsomes and cytosol could catalyze DDC S-methylation. The microsomal activity displayed biphasic substrate kinetics, with apparent Km values for DDC of 7.9 and 1500 microM for the high- and low-affinity activities, respectively. The high-affinity activity had an apparent Km value for S-adenosyl-L-methionine, the methyl donor for the reaction, of 5.8 microM. The thermal inactivation profile and response to methyltransferase inhibitors of the high-affinity microsomal DDC S-methyltransferase activity were similar to those of human liver microsomal TMT. In addition, TMT activity and the activity catalyzing the S-methylation of DDC were highly correlated in 19 individual liver samples (rs = 0.956; P < .0001). Hepatic cytosolic DDC S-methyltransferase activity had an apparent Km value for DDC of 95 microM. The cytosolic enzyme which catalyzed DDC S-methylation and TPMT activity had similar thermal inactivation profiles, similar patterns of response to methyltransferase inhibitors and the two activities coeluted during ion exchange chromatography. Furthermore, the activities of TPMT and cytosolic DDC S-methyltransferase were highly correlated in 20 individual liver samples (rs = 0.963; P < .0001). These results were compatible with the conclusion that both TMT and TPMT could catalyze the S-methylation of DDC in the human liver. Because the activities of both TMT and TPMT are controlled by inheritance, our observations raise the possibility of pharmacogenetic variation in the biotransformation and therapeutic effect of DDC in humans.
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PMID:Diethyldithiocarbamate S-methylation: evidence for catalysis by human liver thiol methyltransferase and thiopurine methyltransferase. 839 51

A tellurite-resistance genetic determinant was isolated from the pea blight pathogen Pseudomonas syringae pathovar pisi by a shotgun strategy involving a tellurite-selective screening in Escherichia coli. A 1.65 kb tellurite resistance insert was obtained and analysed. It harbours a single complete and functional ORF encoding a deduced protein of 24, 445 Da. The deduced AA sequence shows significant similarities with the complete human thiopurine methyltransferase enzyme, a methyltransferase from Synechocystis and a methyltransferase-like sequence from Bordetella pertussis. The encoded thiopurine methyltransferase activity was demonstrated using a radiochemical microassay for the methylation of 6-mercaptopurine. This gene was detected in most P. syringae legume pathogens.
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PMID:A tellurite-resistance genetic determinant from phytopathogenic pseudomonads encodes a thiopurine methyltransferase: evidence of a widely-conserved family of methyltransferases. 956 78

Methyl conjugation is an important pathway in the biotransformation of many exogenous and endogenous compounds. Pharmacogenetic studies of methyltransferase enzymes have resulted in the identification and characterization of functionally important common genetic polymorphisms for catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. In recent years, characterization of these genetic polymorphisms has been extended to include the cloning of cDNAs and genes, as well as a determination of the molecular basis for the effects of inheritance on these methyltransferase enzymes. The thiopurine methyltransferase genetic polymorphism is responsible for clinically significant individual variations in the toxicity and therapeutic efficacy of thiopurine drugs such as 6-mercaptopurine. Phenotyping for the thiopurine methyltransferase genetic polymorphism represents one of the first examples in which testing for a pharmacogenetic variant has entered standard clinical practice. The full functional implications of pharmacogenetic variation in the activities of catechol O-methyltransferase and histamine N-methyltransferase remain to be determined. Finally, experimental strategies used to study methylation pharmacogenetics illustrate the rapid evolution of biochemical, pharmacologic, molecular, and genomic approaches that have been used to determine the role of inheritance in variation in drug metabolism, effect, and toxicity.
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PMID:Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. 1033 Oct 75

Escherichia coli cells expressing the tpm gene encoding the bacterial thiopurine methyltransferase (bTPMT) are shown to methylate selenite and (methyl)selenocysteine into dimethylselenide (DMSe) and dimethyldiselenide (DMDSe). E. coli cells expressing tpm from a gene library cosmid clone (harboring a Pseudomonas syringae insert of about 20 kb) also methylated selenate into DMSe and DMDSe. bTPMT is the first methyltransferase shown to be involved in the methylation of these selenium derivatives.
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PMID:Methylation of inorganic and organic selenium by the bacterial thiopurine methyltransferase. 1200 60

1. Pharmacogenomics is the study of the role of inheritance in variation in the drug response phenotype-a phenotype that can vary from adverse drug reactions at one end of the spectrum to lack of therapeutic efficacy at the other. 2. The thiopurine S-methyltransferase (TPMT) genetic polymorphism represents one of the best characterized and most clinically relevant examples of pharmacogenomics. This polymorphism has also served as a valuable "model system" for studies of the ways in which variation in DNA sequence might influence function. 3. The discovery and characterization of the TPMT polymorphism grew directly out of pharmacogenomic studies of catechol O-methyltransferase (COMT), an enzyme discovered by Julius (Julie) Axelrod and his coworkers. 4. This review will outline the process by which common, functionally significant genetic polymorphisms for both COMT and TPMT were discovered and will use these two methyltransferase enzymes to illustrate general principles of pharmacogenomic research-both basic mechanistic and clinical translational research-principles that have been applied to a series of genes encoding methyltransferase enzymes.
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PMID:Pharmacogenomics: catechol O-methyltransferase to thiopurine S-methyltransferase. 1680 86


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