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)

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

6-Mercaptopurine (6-MP) and methylmercaptopurine ribonucleoside (Me-MPR) are purine anti-metabolites which are both metabolized to methylthio-IMP (Me-tIMP), a strong inhibitor of purine synthesis de novo. Me-MPR is converted directly into Me-tIMP by adenosine kinase. 6-MP is converted into tIMP, and thereafter it is methylated to Me-tIMP by thiopurine methyltransferase, an S-adenosylmethionine (S-Ado-Met)-dependent conversion. S-Ado-Met is formed from methionine and ATP by methionine adenosyltransferase, and is a universal methyl donor, involved in methylation of several macromolecules, e.g. DNA and RNA. Therefore, depletion of S-Ado-Met could result in an altered methylation state of these macromolecules, thereby affecting their functionality, leading to dysregulation of cellular processes and cytotoxicity. In this study the effects of 6-MP and Me-MPR on S-Ado-Met, S-adenosylhomocysteine (S-Ado-Hcy), homocysteine and methionine concentrations are determined. Both drugs cause a decrease in intracellular S-Ado-Met concentrations and an increase in S-Ado-Hcy and methionine concentrations in Molt F4 human malignant lymphoblasts. The effects of both 6-MP and Me-MPR can be ascribed to a decreased conversion of methionine into S-Ado-Met, due to the ATP depletion induced by the inhibition of purine synthesis de novo by Me-tIMP. Both 6-MP and Me-MPR thus affect the methylation state of the cells, and this may result in dysregulation of cellular processes and may be an additional mechanism of cytotoxicity for 6-MP and Me-MPR.
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PMID:Decrease in S-adenosylmethionine synthesis by 6-mercaptopurine and methylmercaptopurine ribonucleoside in Molt F4 human malignant lymphoblasts. 799 28

1. 2-(Allylthio)pyrazine (2-AP) has been demonstrated to protect the liver against toxicants by inhibiting CYP2E1 activity. Since 2-mercaptopyrazine (2-MP) is presumed to be a metabolite of 2-AP, the experiments were performed to determine whether rat liver microsomal and/or cytosolic preparations could catalyse the S-methylation of 2-MP. 2. It was found that both rat liver microsomes and cytosol could catalyse the S-methylation of 2-MP. The microsomal activity displayed biphasic substrate kinetics, with apparent Km = 8.44+/-2.68 and 417+/-74 microM for the high- and low-affinity activities respectively. The high-affinity activity had an apparent Km for S-adenosyl-L-methionine (Ado-Met) of 3.52 microM. The cytosolic activity also displayed biphasic substrate kinetics, with apparent Km of 3.26+/-0.62 and 91.6+/-23.1 microM for the high- and low-affinity activities respectively. 3. The microsomal S-methylation of 2-MP was inhibited by 2,3-dichloro-alpha-methylbenzylamine (DCMB), SKF-525A and benzylamine, known microsomal thiol methyltransferase (TMT) inhibitors, whereas cytosolic activity was inhibited by anisic acid and 3-chlorobenzoate, which also inhibit cytosolic thiopurine methyltransferase (TPMT). Both activities were inhibited by S-adenosyl-L-homocysteine (Met-Hcy). 4. These results suggest that both TMT and TPMT may be involved in the in vivo methylation of 2-MP.
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PMID:S-methylation of 2-mercaptopyrazine in rat liver microsomes and cytosol. 1054 51

S-Adenosyl-L-methionine (AdoMet) which is biologically synthesized by AdoMet synthetase bears an S configuration at the sulfur atom. The chiral sulfonium spontaneously racemizes to form a mixture of S and R isomers of AdoMet under physiological conditions or normal storage conditions. The chirality of AdoMet greatly affects its activity; the R isomer is not accepted as a substrate for AdoMet-dependent methyltransferases. We report a stereospecific colorimetric assay for (S,S)-adenosylmethionine quantification based on an enzyme-coupled reaction in which (S,S)-AdoMet reacts with 2-nitro-5-thiobenzoic acid to form AdoHcy and 2-nitro-5-methylthiobenzoic acid. The transformation is catalyzed by recombinant human thiopurine S-methyltransferase (TPMT, EC 2.1.1.67) and is associated with a large spectral change at 410 nm. Accumulation of the S-adenosylhomocysteine (AdoHcy) product, a feedback inhibitor of TPMT, slows the assay. AdoHcy nucleosidase (EC 3.2.2.9) irreversibly cleaves AdoHcy to adenine and S-ribosylhomocysteine, significantly shortening the assay time to less than 10 min. The assay is linear from 5 to at least 60 microM (S,S)-AdoMet.
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PMID:A stereospecific colorimetric assay for (S,S)-adenosylmethionine quantification based on thiopurine methyltransferase-catalyzed thiol methylation. 1241 50

Human thiopurine S-methyltransferase (TPMT) exhibits considerable person-to-person variation in activity to thiopurine drugs. We have produced an N-terminal truncation of human TPMT protein, crystallized the protein in complex with the methyl donor product S-adenosyl-L-homocysteine, and determined the atomic structure to the resolution of 1.58 and 1.89 A, respectively, for the seleno-methionine incorporated and wild type proteins. The structure of TPMT indicates that the naturally occurring amino acid polymorphisms scatter throughout the structure, and that the amino acids whose alteration have the most influence on function are those that form intra-molecular stabilizing interactions (mainly van der Waals contacts). Furthermore, we have produced four TPMT mutant proteins containing variant alleles of TPMT*2, *3A, *3B, and *3C and examined the structure-function relationship of the mutant proteins based on their expression and solubility in bacteria and their thermostability profile.
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PMID:Structural basis of allele variation of human thiopurine-S-methyltransferase. 1724 78