Methyl conjugation is an important pathway in the biotransformation of many drugs, other xenobiotic compounds, neurotransmitters and hormones. During the past two decades, the applicant's laboratory has systematically explored the pharmacogenetics and pharmacogenomics of enzymes that catalyze the methyl conjugation of """"""""small molecules"""""""". In pursuit of that goal, we have applied the techniques of molecular biology and genomics to clone and characterize genes encoding methyltransferase enzymes in humans and other species and have then identified both single nucleotide polymorphisms (SNPs) and other DNA sequence variations of functional importance for individual variation in methylation. That approach has resulted in the identification of a series of common, medically and biologically significant genetic polymorphisms for methyltransferase enzymes. Of special importance are the thiopurine S-methyltransferase (TPMT), histamine N-methyltransferase (HNMT) and catechol O-methyltransferase (COMT) genetic polymorphisms that we discovered and characterized. All of these common """"""""pharmacogenetic"""""""" variations contribute to individual differences in response to drug therapy and/or the pathophysiology of human disease. These polymorphisms involve nonsynonymous cSNPs in the open reading frames (ORFs) of the genes encoding TPMT, HNMT and COMT - i.e., SNPs that change encoded amino acids. Furthermore, the variant alleles for all three of these common genetic polymorphisms result in decreased levels of enzyme protein. We now propose to explore molecular mechanisms by which nonsynonymous cSNPs result in decreases in the quantity of enzyme protein - a common functional consequence of this type of polymorphism, not just for enzymes that catalyze methylation but also for other drug-metabolizing enzymes. We also propose to move our studies of methylation pharmacogenetics """"""""beyond the ORF"""""""" to include the functional characterization of common genetic variation within the 5'-flanking regions of TPMT and COMT. The results of these experiments will increase our understanding of molecular genetic mechanisms responsible for functionally significant individual variation in methyl conjugation, and they will help make it possible to predict individual variations in the methylation and, therefore, the effects of drugs, xenobiotics, neurotransmitters and hormones that are metabolized by this phase II pathway of biotransformation. ? ?
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