Directional probes of the hydrophobic component of the aromatic ring binding site of norepinephrine N-methyltransferase.
We investigated the directional nature of the bulk tolerance and hydrophobic binding in the aromatic ring binding region of the active site of norepinephrine N-methyltransferase (NMT) by comparing the substrate and inhibitor activities of m- and p-phenyl-substituted derivatives of amphetamine, phenylethanolamine, and alpha-methylbenzylamine. The para isomers of amphetamine and phenylethanolamine displayed significantly greater activities as inhibitor and substrate, respectively, than the meta isomers, which indicated that the bulk tolerance was near the para position. For benzylamines, the greatest inhibitory activity was observed for the meta isomer, demonstrating a significant difference in the binding requirements for phenylethylamines and benzylamines. These findings are consistent with a two-state model for the NMT active site that has been proposed elsewhere to account for its ability to bind both benzylamines and phenylethylamines in a fully extended side-chain conformation.
D000662:Amphetamines / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D001665:Binding Sites; D055598:Chemical Phenomena; D002621:Chemistry; D007700:Kinetics; D010627:Phenethylamines / Q000494:pharmacology; D010625:Phenylethanolamine N-Methyltransferase / Q000302:isolation & purification*
D000662:Amphetamines; D001596:Benzylamines; D010627:Phenethylamines; D010625:Phenylethanolamine N-Methyltransferase