2024 AIChE Annual Meeting

Exploration of Tryptophan Modifying Enzymes: An Expansion of Nonnatural Psilocybin Derivatives

Current medical treatments for mental illnesses such as anxiety, depression, and post-traumatic stress disorder are often limited and can cause many unwanted side effects. The lack of accessibility to effective mental health treatment across the globe calls for new and creative solutions. A promising alternative has been found in psychedelic treatment, mainly psilocybin. Psilocybin is naturally found in over 200 species of ‘magic’ mushrooms, and has recently been the subject of a growing number of clinical studies testing its ability to treat mental health disorders including depression, anxiety, and PTSD.


In E. coli, the biosynthesis of psilocybin starts with the formation of 4-hydroxytryptophan (4-HTP) by tryptophan synthase from a 4-hydroxyindole supplement. 4-HTP is then decarboxylated, phosphorylated, and methylated to form the final psilocybin product. The incorporation of new tryptophan modifying enzymes into the base psilocybin biosynthetic pathway has the potential to create new biosynthetic psychedelic derivatives to increase the drug candidate pool for development of next-generation mental illness treatment. We have evaluated the activity of halogenases, which catalyze the incorporation of chlorine or bromine atoms onto their substrates, as well as prenyltransferases, which add a dimethylallyl group onto tryptophan and indole derivatives. Both of these directions have the ability to result in novel, new-to-nature compounds which could be promising drug candidates. We have successfully shown both halogenase and prenyltransferase activity on 4-HTP, and more importantly have created chlorinated psilocybin compounds through the use of an E. coli co-culture. This observation is the first example of de novo production of chloropsilocybin in a recombinant host and is a step forward in the creation of bioproduction approaches for pharmaceutical drug candidates for mental health treatment.