Human indole(ethyl)amine-N-methyltransferase (hINMT) catalyzed methylation of tryptamine, dimethylsulfide and dimethylselenide is enhanced under reducing conditions - A comparison between 254C and 254F, two common hINMT variants

Abstract

Phenylalanine and cysteine comprise common miss-sense variants (i.e., single nucleotide polymorphisms [SNPs]) at amino acid position 254 of the human indole(ethyl)amine-N-methyltransferase (hINMT). The phenylalanine variant, which occurs in linkage disequilibrium with two 3’ UTR SNPs, has been reported to associate with elevated urine levels of trimethylselenonium (TMSe), the Se-methylated product of volatile dimethylselenide. hINMT allozymes expressing either cysteine (254C) or phenylalanine (254F) at position 254 were compared for enzyme activity (i.e., K m and V max ) towards the INMT substrates tryptamine, dimethylsulfide (DMS) and dimethylselenide (DMSe) in vitro . The SNP 254C had a higher V max for DMS and tryptamine in the presence of reducing agent than in its absence. Conversely, V max for 254F was insensitive to the presence or absence of reducing agent for these substrates. SNP 254F showed a lower K m for tryptamine in the absence of reducing agent than 254C. No statistically significant difference in V max or K m was observed between 254C and 254F allozymes in the presence of reducing agent for DMSe, The K m values for DMSe methylation were about 10-fold (254C) or 6-fold (254F) more favorable than for tryptamine methylation with reducing agent present. These findings indicated that: 1) That phenylalanine at position 254 renders hINMT methylation of substrates DMS and tryptamine insensitive to a non reducing environment. 2) That human INMT harbors significant thioether-S-methyltransferase (TEMT) activity with a higher affinity for DMSe than tryptamine, 3) The reduction of a 44C/254C disulfide bond in hINMT that increases V max is proposed.

Production of a Urinary Selenium Metabolite, Trimethylselenonium, by Thiopurine S-Methyltransferase and Indolethylamine N-Methyltransferase

“…18,19 Previous works suggested that mouse and human INMT proteins drove the methylation of dimethylsulfide, dimethylselenide, and dimethyltelluride as substrates. 20,21 However, it is still unclear how INMT commits to produce TMSe for urinary Se excretion.…”

“…Indolethylamine N -methyltransferase (INMT) is another methyltransferase that catalyzes double methylation of tryptamine to produce N , N -dimethyltryptamine . The TMSe concentration in blood and urine correlated with single nucleotide polymorphisms in the INMT gene by a genome wide association study between the TMSe-producing and nonproducing individuals. , Previous works suggested that mouse and human INMT proteins drove the methylation of dimethylsulfide, dimethylselenide, and dimethyltelluride as substrates. , However, it is still unclear how INMT commits to produce TMSe for urinary Se excretion.…”

Indolethylamine-N-Methyltransferase Inhibits Proliferation and Promotes Apoptosis of Human Prostate Cancer Cells: A Mechanistic Exploration

“…Therefore, the research and development of biomarkers associated with prostate cancer metastasis, including prostate-specific antigen (PSA), androgen receptor splice variant 7 (ARV7), and transforming growth factor-beta (TGFβ), might guide the early treatment decision of tumor metastasis and significantly improve outcomes (Kretschmer and Tilki, 2017;Manca et al, 2017;Bastos and Antonarakis, 2018). Indolethylamine-N-methyltransferase (INMT) is a methyltransferase that regulates the N-methylation of tryptamine family proteins (Chu et al, 2014;Torres et al, 2019). It is associated with the development and activity of the nervous system and participates in the detoxification of selenium compounds (Kim et al, 2015;Kuehnelt et al, 2015).…”

“…Indolethylamine-N-methyltransferase (INMT) is a methyltransferase that regulates the N-methylation of tryptamine family proteins ( Chu et al, 2014 ; Torres et al, 2019 ). It is associated with the development and activity of the nervous system and participates in the detoxification of selenium compounds ( Kim et al, 2015 ; Kuehnelt et al, 2015 ).…”

Low expression of INMT is associated with poor prognosis but favorable immunotherapy response in lung adenocarcinoma

“…Indolethylamine N-methyltransferase (INMT) is a methyltransferase that regulates the tryptophan metabolic pathway by catalyzing the N-methylation of tryptamine and structurally related compounds ( Chu et al, 2014 ; Torres et al, 2019 ). As a thioether S-methyltransferase, it also plays an important role in the detoxification of selenium compounds ( Kuehnelt et al, 2015 ).…”