Tryptamines are neurotransmitters and psychoactive compounds found in many organisms. Psilocybin, a tryptamine, shows therapeutic potential for depression and anxiety, but current extraction methods are labor-intensive and costly. Biocatalysis—using enzymes—offers a sustainable alternative for synthesizing psilocybin and related tryptamines. Understanding psilocybin biosynthesis pathways can improve synthetic methods and industrial production. This review highlights biocatalysis's potential to advance tryptamine biosynthesis knowledge and enable high-purity production for therapy and research.
N-methylated tryptamines like psilocybin and DMT show promise as treatments for mental health disorders, driving interest in biosynthetic production. This work characterized two enzymes from tryptamine biosynthesis: TrpM, a tryptophan N-methyltransferase from Psilocybe serbica, and PsiD, a decarboxylase from the psilocybin pathway. TrpM was able to N-methylate 4-hydroxytryptophan, a non-native amino acid. However, incorporating TrpM into a functional psilocybin pathway was blocked because PsiD could not use N,N-dimethyl-4-hydroxytryptophan as a substrate under the tested conditions, despite acting on N-methylated and 4-hydroxylated tryptophan derivatives separately. These findings expand the known substrates for TrpM and PsiD, increasing the diversity of tryptamine biosynthetic products.