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Molecular Pharmacology, Vol 6, 691-696, Copyright © 1970 by the American Society for Pharmacology and Experimental Therapeutics

Catechol O-Methyltransferase

III. m- and p-O-Methylation of Catecholamines and Their Metabolites

C. R. CREVELING 1, N. DALGARD 1, H. SHIMIZU 1, and J. W. DALY 1

1 National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland 20014

In vitro, O-methylation of physiological substrates of catechol O-methyltransferase (EC 2.1.1.6) such as (nor)epinephrine, dopamine, 3,4-dihydroxyphenylacetic acid, 3,4-dihydroxymandelic acid, 3,4-dihydroxyphenylethanol, 3,4-dihydroxyphenylglycol, 3,4-dihydroxybenzoic acid, N-acetyldopamine, N-acetylnorepinephrine, and 3,4-dihydroxyphenylalanine affords mixtures of m- and p-O-methyl derivatives. The extent of p-methylation relative to m-methylation is low with substrates containing an ionized moiety in the ring substituent, i.e., amino acids, acids, and amines, and increases as the polar (hydrophilic) character of the ring substituent is decreased. With a nonpolar substituent, as in 4-ethylcatechol, the ratio of meta to para products is 1:1. The results suggest the presence of a nonpolar region in the catechol-binding site of catechol O-methyltransferase which militates against binding of polar substrates in the orientation necessary for p-methylation, which nonpolar substrates would appear to bind in a random fashion, resulting in the formation of nearly equal amounts of m- and p-O-methylated products. No change in the meta:para ratios was observed during more than 400-fold purification of catechol O-methyltransferase, suggesting that only one enzyme is involved in both m- and p-O-methylation.

Submitted on July 27, 1970




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