Methylation of Thiols and Thioethers by Human Indolethylamine‐N Methyl Transferase

Abstract

Indolethylamine‐N MethylTransferase (INMT) is a small molecule N‐methyltransferase that transfer methyl groups from S‐Adenosyl‐L‐Methionine (SAM) to indoleamines. Methylation of tryptamine produces the hallucinogen, N,N‐dimethyltryptamine (DMT), and methylated serotonin generates bufotenin. In animals, the endogenous production of DMT has been proposed to be a regulator of the Sigma‐1 Receptor and for mood and cognition through activation of serotonin and other receptors. In contrast to the human and rabbit INMT, mouse INMT (referred to as ThioEtherMethylTransferase or TEMT) has been independently characterized and methylates thioethers, dimethyl selenide and dimethyl telluride to produce their respective “onium “ products. TEMT was suggested to be involved in the detoxification of sulfides, selenides, and tellurides. The S‐methylating activities of human and rabbit INMT have not been characterized. We evaluated the efficiency of human INMT to produce methylated sulfur containing compounds. Pure human INMT methylated both thiols and thioethers including cysteamine and 2‐(thiomethyl)ethylamine (MTEA). The Km for MTEA methylation at pH 7.2 was approximately 1.2 mM. We also compared the N‐ and S‐methylating activities of human INMT over a pH range of 6.3‐8.0 and found that acidic conditions favored S‐methylation of MTEA and alkaline conditions favored N‐methylation of tryptamine. The methylations of tryptamine and MTEA were approximately equal at pH 6.8. These data suggest a mechanism of cellular regulation of the bifunctional N‐ and S‐methylating activities of human INMT that may depend on the prevailing acidic and basic conditions of certain mammalian tissues.