Evaluation of TrpM and PsiD substrate promiscuity reveals new biocatalytic capabilities
Biotechnology Progress – June 18, 2024
Source: OpenAlex
Summary
Psychedelics like psilocybin and other tryptamines, natural alkaloids with complex biochemistry, offer promise for mental health treatments. Their biosynthesis, a form of chemical synthesis, is being refined for drug studies. This involves understanding enzymes like TrpM and PsiD, crucial for converting tryptophan derivatives. TrpM successfully N-methylates 4-hydroxytryptophan. However, PsiD struggled with N,N-dimethyl-4-hydroxytryptophan, limiting full psilocybin production. This chemistry expands our knowledge of tryptamines, vital for developing new drugs and understanding natural product roles in health, including potential gut microbiota interactions.
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.