Indolethylamine N-methyltransferase (INMT) is not essential for endogenous tryptamine-dependent methylation activity in rats

Indolethylamine N -methyltransferase (INMT) is a transmethylation enzyme that utilizes the methyl donor S -adenosyl-L-methionine to transfer methyl groups to amino groups of small molecule acceptor compounds. INMT is best known for its role in the biosynthesis of N,N -Dimethyltryptamine (DMT), a psy...

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Published in:Scientific reports 2023-01, Vol.13 (1), p.280-280, Article 280
Main Authors: Glynos, Nicolas G., Carter, Lily, Lee, Soo Jung, Kim, Youngsoo, Kennedy, Robert T., Mashour, George A., Wang, Michael M., Borjigin, Jimo
Format: Article
Language:English
Subjects:
631/378
631/443
631/45
631/45/607/1172
631/92
Amino groups
Animals
Biosynthesis
Chromatography
Enzymes
High-performance liquid chromatography
Humanities and Social Sciences
Humans
Liquid chromatography
Mammals
Mass spectrometry
Mass spectroscopy
Methionine
Methylation
Methyltransferase
multidisciplinary
N,N-Dimethyltryptamine - chemistry
N-Methyltransferase
Rabbits
Rats
Science
Science (multidisciplinary)
Thin layer chromatography
Tryptamine
Tryptamines
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Summary:Indolethylamine N -methyltransferase (INMT) is a transmethylation enzyme that utilizes the methyl donor S -adenosyl-L-methionine to transfer methyl groups to amino groups of small molecule acceptor compounds. INMT is best known for its role in the biosynthesis of N,N -Dimethyltryptamine (DMT), a psychedelic compound found in mammalian brain and other tissues. In mammals, biosynthesis of DMT is thought to occur via the double methylation of tryptamine, where INMT first catalyzes the biosynthesis of N -methyltryptamine (NMT) and then DMT. However, it is unknown whether INMT is necessary for the biosynthesis of endogenous DMT. To test this, we generated a novel INMT-knockout rat model and studied tryptamine methylation using radiometric enzyme assays, thin-layer chromatography, and ultra-high-performance liquid chromatography tandem mass spectrometry. We also studied tryptamine methylation in recombinant rat, rabbit, and human INMT. We report that brain and lung tissues from both wild type and INMT-knockout rats show equal levels of tryptamine-dependent activity, but that the enzymatic products are neither NMT nor DMT. In addition, rat INMT was not sufficient for NMT or DMT biosynthesis. These results suggest an alternative enzymatic pathway for DMT biosynthesis in rats. This work motivates the investigation of novel pathways for endogenous DMT biosynthesis in mammals.
ISSN:2045-2322
2045-2322
DOI:10.1038/s41598-023-27538-y