Evaluation of TrpM and PsiD substrate promiscuity reveals new biocatalytic capabilities
Xin Wang, Fiona C. Kanis, Caroline N. Broude, Elle B. Hellwarth, William E. Gibbons, Abhishek K. Sen, Alexandra M. Adams, J. Andrew Jones
Biotechnology Progress June 18, 2024 DOI: 10.1002/btpr.3492 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Topics | Psilocybin |
| Keywords | Biosynthesis Tryptamines Biochemistry Tryptophan Enzyme |
| Citations | 2 |
| Key findings | TrpM can N-methylate 4-hydroxytryptophan, but PsiD cannot use N,N-dimethyl-4-hydroxytryptophan as substrate under tested conditions, preventing a functional psilocybin pathway with this combination. |
Abstract
Abstract N ‐methylated tryptamines, such as the hallucinogenic natural products, psilocybin and N,N ‐dimethyltryptamine (DMT), are gaining interest from the medical community due to their potential as next generation treatments for mental health disorders. The clinical relevance of these compounds has driven scientists to develop biosynthetic production routes to a number of tryptamine drug candidates, and efforts are ongoing to expand and further develop these biosynthetic capabilities. To that end, we have further characterized the substrate preferences of two enzymes involved in tryptamine biosynthesis: TrpM, a tryptophan N ‐methyltransferase from Psilocybe serbica , and PsiD, the gateway decarboxylase of the psilocybin biosynthesis pathway. Here, we show that TrpM can N ‐methylate the non‐native amino acid substrate, 4‐hydroxytryptophan, a key intermediate in the Escherichia coli ‐based recombinant psilocybin biosynthesis pathway. However, the ability to incorporate TrpM into a functional psilocybin biosynthesis pathway was thwarted by PsiD's inability to use N,N ‐dimethyl‐4‐hydroxytryptophan as substrate, under the culturing conditions tested, despite demonstrating activity on N ‐methylated and 4‐hydroxylated tryptophan derivatives individually. Taken together, this work expands upon the known substrates for TrpM and PsiD, further increasing the diversity of tryptamine biosynthetic products.
Comparable studies
Other experimental studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers | 1998 | Experimental study | |
| Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... | 2015 | Validation study using pooled data from five laboratory experiments | n = 184 |
| Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants | 2013 | Experimental study | |
| Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... | 2020 | Long-term within-subjects follow-up analysis | n = 15 |
| Enzymatic Synthesis of Psilocybin | 2017 | Laboratory study |
Citations in the library
Cited by 3
- Exploring the biocatalysis of psilocybin and other tryptamines: Enzymatic pathways, synthetic strategies, and industrial implications Biotechnology Progress October 4, 2024
- Pathway engineering for the biosynthesis of psychedelics Current Opinion in Biotechnology May 15, 2025
- Reconstituting a two-step pathway for N,N-dimethyltryptamine (DMT) biosynthesis in bacteria Metabolic Engineering Communications July 1, 2026
Cites 15
- Enzymatic Synthesis of Psilocybin Angewandte Chemie International Edition August 1, 2017
- Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives Metabolic Engineering March 26, 2020
- Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi Metabolic Engineering May 26, 2018
- In vivo production of psilocybin in E. coli Metabolic Engineering September 21, 2019
- Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin Journal of Natural Products February 20, 2020
and 10 more in the library