Inhibition of histamine methyltransferase by serotonin and chlorpromazine derivatives: electronic aspects

Summary The kinetics of inhibition of histamine methyltransferase (S-adenosylmethio-nine:histamine N-methyltransferase, EC 2.1.1.8) by serotonin, chlorpromazine and a number of their derivatives has been investigated. Lineweaver-Burk plots showed that these compounds act as non-competitive inhibitors with Ki values ranging from 13 to 130 μM. Dialysis experiments showed the inhibition to be kinetically reversible. The electronic nature of the complex formed between enzyme and inhibitor has been investigated by molecular-orbital calculations of selected reactivity indices of these two groups of compounds. The principal characteristic of the electronic configuration of these compounds which appears to determine their relative Ki values is their ability to donate electrons, as measured by the energy of their highest filled molecular orbitals. It is suggested, on the basis of the data presented, that the formation of the enzyme-inhibitor complex involves partial or total transfer of one or more electrons from the inhibitor to the enzyme.