Catechol-O-methyltransferase: substrate-specificity and stereoselectivity for beta-adrenoceptor agents.
Isoprenaline, isoetharine, rimiterol, dobutamine and nadolol were investigated as substrates for purified pig-liver catechol-O-methyltransferase using a sensitive spectrophotometric assay. Kinetic parameters, Km and Vmax, were defined and the apparent first-order rate constant (Vmax/Km) was derived. On the basis of the apparent first-order rate constant, rimiterol was found to be a 1.5-fold and dobutamine a 5-fold better substrate for catechol-O-methyltransferase than isoprenaline; isoetharine shows no improvement over isoprenaline. Nadolol is not a substrate for catechol-O-methyltransferase. O-Methylation of isoprenaline- and noradrenaline-enantiomers was found to be stereoselective: catechol-O-methyltransferase shows selectivity towards the laevo (-) isomer with respect to the (+) form or racemic mixture. The investigation indicated stereochemical and steric determinants important in the interaction of catechol-O-methyltransferase with physiologically and clinically important beta-adrenoceptor agents.
Raxworthy
M J
MJ
Youde
I R
IR
Gulliver
P A
PA
D000319:Adrenergic beta-Antagonists / Q000378:metabolism; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D004280:Dobutamine / Q000378:metabolism; D007528:Isoetharine / Q000378:metabolism; D007545:Isoproterenol / Q000378:metabolism; D007700:Kinetics; D008745:Methylation; D009248:Nadolol; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000378:metabolism; D011412:Propanolamines / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013552:Swine
D000319:Adrenergic beta-Antagonists; D010880:Piperidines; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D004280:Dobutamine; D009248:Nadolol; D002394:Catechol O-Methyltransferase; D007545:Isoproterenol; D009638:Norepinephrine; D007528:Isoetharine