Enzymatic Synthesis of Psilocybin

Psilocybin is the psychotropic tryptamine-derived natural product of Psilocybe carpophores, the so-called magic mushrooms. Although its structure has been known for 60years, 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.