Catechol O-methyltransferase (COMT) typically metabolizes catecholamines and estrogens, forming mixtures of ortho and para methoxy metabolites118 Drug substrates include L-dopa, 2-hydroxy ethinylestradiol and isoproteranol and COMT inhibitors have therapeutic value in the treatment of Parkinsonism. The enzyme is the product of a single gene located on chromosome 22q11.2, but two forms of the protein exist: soluble COMT (S-COMT, ~25 kDa) and membrane-bound COMT (M-COMT, ~30kDa), whose additional 50 amino acids provide the hydrophobic anchor for membrane localization. S-COMT predominates in peripheral tissues and M-COMT is the main form of the enzyme in brain tissue.119 COMT activity is inherited in an autosomal recessive manner. Individuals with low activity inherit a form of the enzyme that is thermolabile. A single G to A transition at codon 108/158 of the cytosolic/membrane gene results in a Val to Met substitution which forms the molecular basis for the well-recognized interindividual variation in the metabolism and response to the antihypertensive drug, a-methyldopa.117
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