Enzymatic Synthesis of Psilocybin

Psilocybin, the psychoactive compound in magic mushrooms, is synthesized from tryptophan by four fungal enzymes: PsiD (a decarboxylase), PsiK (a kinase), PsiM (a methyltransferase), and PsiH (a monooxygenase). Using a combined reaction of PsiD, PsiK, and PsiM, the authors produced psilocybin enzymatically from 4-hydroxy-L-tryptophan in fewer steps than previously possible. This work identifies the complete biosynthetic pathway, which had been unknown for 60 years, and may enable biotechnological production of psilocybin for pharmaceutical use.

Study at a glance

Abstract

Abstract Psilocybin is the psychotropic tryptamine‐derived natural product of Psilocybe carpophores, the so‐called “magic mushrooms”. Although its structure has been known for 60 years, the enzymatic basis of its biosynthesis has remained obscure. We characterized four psilocybin biosynthesis enzymes, namely i) PsiD, which represents a new class of fungal l ‐tryptophan decarboxylases, ii) PsiK, which catalyzes the phosphotransfer step, iii) the methyltransferase PsiM, catalyzing iterative N‐methyl transfer as the terminal biosynthetic step, and iv) PsiH, a monooxygenase. In a combined PsiD/PsiK/PsiM reaction, psilocybin was synthesized enzymatically in a step‐economic route from 4‐hydroxy‐ l ‐tryptophan. Given the renewed pharmaceutical interest in psilocybin, our results may lay the foundation for its biotechnological production.