Noncompetitive inhibition of indolethylamine-N-methyltransferase by N,N-dimethyltryptamine and N,N-dimethylaminopropyltryptamine.
Uyen B Chu, Sevahn K Vorperian, Kenneth Satyshur, Kelsey Eickstaedt, Nicholas V. Cozzi, Timur A. Mavlyutov, Abdol R. Hajipour, Arnold E. Ruoho
Biochemistry May 13, 2014 DOI: 10.1021/bi500175p (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro enzyme kinetics study Peer reviewed |
|---|---|
| Population | Rabbit lung indolethylamine-N-methyltransferase (rabINMT) enzyme, with comparisons to human PNMT and NNMT |
| Topics | 5-MeO-DMT DMT |
| Key points | DMT inhibits rabbit INMT by a mixed competitive and noncompetitive mechanism against tryptamine, while the novel derivative PDAT inhibits it purely noncompetitively with a Ki of 84 μM and shows selectivity over human PNMT and NNMT. The authors argue the noncompetitive mechanism implies an allosteric inhibitory site, and modeling points to an N-terminal helix-loop-helix region as a possible binding site. |
Abstract
Indolethylamine-N-methyltransferase (INMT) is a Class 1 transmethylation enzyme known for its production of N,N-dimethyltryptamine (DMT), a hallucinogen with affinity for various serotonergic, adrenergic, histaminergic, dopaminergic, and sigma-1 receptors. DMT is produced via the action of INMT on the endogenous substrates tryptamine and S-adenosyl-l-methionine (SAM). The biological, biochemical, and selective small molecule regulation of INMT enzyme activity remain largely unknown. Kinetic mechanisms for inhibition of rabbit lung INMT (rabINMT) by the product, DMT, and by a new novel tryptamine derivative were determined. After Michaelis-Menten and Lineweaver-Burk analyses had been applied to study inhibition, DMT was found to be a mixed competitive and noncompetitive inhibitor when measured against tryptamine. The novel tryptamine derivative, N-[2-(1H-indol-3-yl)ethyl]-N',N'-dimethylpropane-1,3-diamine (propyl dimethyl amino tryptamine or PDAT), was shown to inhibit rabINMT by a pure noncompetitive mechanism when measured against tryptamine with a Ki of 84 μM. No inhibition by PDAT was observed at 2 mM when it was tested against structurally similar Class 1 methyltransferases, such as human phenylethanolamine-N-methyltransferase (hPNMT) and human nicotinamide-N-methyltransferase (hNNMT), indicating selectivity for INMT. The demonstration of noncompetitive mechanisms for INMT inhibition implies the presence of an inhibitory allosteric site. In silico analyses using the computer modeling software Autodock and the rabINMT sequence threaded onto the human INMT (hINMT) structure (Protein Data Bank entry 2A14 ) identified an N-terminal helix-loop-helix non-active site binding region of the enzyme. The energies for binding of DMT and PDAT to this region of rabINMT, as determined by Autodock, were -6.34 and -7.58 kcal/mol, respectively. Assessment of the allosteric control of INMT may illuminate new biochemical pathway(s) underlying the biology of INMT.
Comparable studies
Other preclinical and animal studies on 5-MeO-DMT, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelic N,N-dimethyltryptamine and 5-methoxy-N,N-dimethyltryptamine modulate innate and adaptive inflammatory responses through the sigma-1 receptor of human monocyte-derived dendritic cells. Human primary monocyte-derived dendritic cells | 2014 | In vitro study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| Hallucinogen-like actions of 5-methoxy-N,N-diisopropyltryptamine in mice and rats. Mice and rats | 2006 | Preclinical study | |
| Agonist Properties of N,N-Dimethyltryptamine at Serotonin 5-HT2A and 5-HT2C Receptors Rats and transfected fibroblasts | 1998 | Experimental study | |
| Subtypes of the 5-HT receptor mediating the behavioural responses to 5-methoxy-N,N-dimethyltryptamine in the rat Intact rats and rats depleted of monoamines with reserpine | 1985 | Experimental study |
Citations in the library
Cited by 17
- Dark Classics in Chemical Neuroscience:N,N-Dimethyltryptamine (DMT) ACS Chemical Neuroscience July 23, 2018
- N,N -dimethyltryptamine and the pineal gland: Separating fact from myth Journal of Psychopharmacology 2018
- Exploring DMT: Endogenous role and therapeutic potential. Neuropharmacology May 1, 2025
- N,N‐dimethyltryptamine and Amazonian ayahuasca plant medicine Human Psychopharmacology: Clinical and Experimental February 17, 2022
- Indolethylamine-N-methyltransferase Polymorphisms: Genetic and Biochemical Approaches for Study of Endogenous N,N,-dimethyltryptamine Frontiers in Neuroscience April 23, 2018
and 12 more in the library
Cites 17
- The Hallucinogen N,N -Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator Science February 13, 2009
- The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain. European Journal of Pharmacology March 22, 2007
- Enzymatic Formation of Psychotomimetic Metabolites from Normally Occurring Compounds Science August 4, 1961
- Dimethyltryptamine and other hallucinogenic tryptamines exhibit substrate behavior at the serotonin uptake transporter and the vesicle monoamine transporter. Journal of Neural Transmission September 12, 2009
- A critical review of reports of endogenous psychedelic N, N-dimethyltryptamines in humans: 1955-2010. Drug Testing and Analysis 2012
and 12 more in the library