Iterative l‐Tryptophan Methylation in Psilocybe Evolved by Subdomain Duplication
ChemBioChem – August 11, 2018
Source: OpenAlex
Summary
A surprising discovery in fungal biology reveals that *Psilocybe serbica* mushrooms utilize a distinct biochemical pathway for modifying l-tryptophan, separate from psilocybin biosynthesis. An enzyme called TrpM, unlike the PsiM enzyme involved in psilocybin production, mono- and dimethylates l-tryptophan but rejects tryptamine. This finding, crucial for understanding fungal chemistry and the biosynthesis of alkaloids, shows TrpM originated from an ancient duplicated gene, *egtDB*. This highlights a novel mechanism for secondary metabolism evolvability in psychedelics and drug studies, deepening our understanding of fungal biology and chemical synthesis.
Abstract
Abstract Psilocybe mushrooms are best known for their l ‐tryptophan‐derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the “magic” mushroom Psilocybe serbica also mono‐ and dimethylates l ‐tryptophan, which is incompatible with the specificity of PsiM. Here, a second methyltransferase, TrpM, was identified and functionally characterized. Mono‐ and dimethylation activity on l ‐tryptophan was reconstituted in vitro, whereas tryptamine was rejected as a substrate. Therefore, we describe a second l ‐tryptophan‐dependent pathway in Psilocybe that is not part of the biosynthesis of psilocybin. TrpM is unrelated to PsiM but originates from a retained ancient duplication event of a portion of the egtDB gene that encodes an ergothioneine biosynthesis enzyme. During mushroom evolution, this duplicated gene was widely lost but re‐evolved sporadically and independently in various genera. We propose a new secondary metabolism evolvability mechanism, in which weakly selected genes are retained through preservation in a widely distributed, conserved pathway.