Details

Autor(en) / Beteiligte

• Flower, Jessica E.
• Gibbons, William J.
• Adams, Alexandra M.
• Wang, Xin
• Broude, Caroline N.
• Jones, J. Andrew

Titel

Biosynthesis of psilocybin and its nonnatural derivatives by a promiscuous psilocybin synthesis pathway in Escherichia coli

Ist Teil von

• Biotechnology and bioengineering, 2023-08, Vol.120 (8), p.2214-2229

Ort / Verlag

United States: Wiley Subscription Services, Inc

Erscheinungsjahr

2023

Quelle

Wiley Online Library Journals Frontfile Complete

Beschreibungen/Notizen

• Traditional psychedelics are undergoing a transformation from recreational drugs, to promising pharmaceutical drug candidates with the potential to provide an alternative treatment option for individuals struggling with mental illness. Sustainable and economic production methods are thus needed to facilitate enhanced study of these drug candidates to support future clinical efforts. Here, we expand upon current bacterial psilocybin biosynthesis by incorporating the cytochrome P450 monooxygenase, PsiH, to enable the de novo production of psilocybin as well as the biosynthesis of 13 psilocybin derivatives. The substrate promiscuity of the psilocybin biosynthesis pathway was comprehensively probed by using a library of 49 single‐substituted indole derivatives, providing biophysical insights to this understudied metabolic pathway and opening the door to the in vivo biological synthesis of a library of previously unstudied pharmaceutical drug candidates. This study reports the development of a bacterial system capable of the de novo biosynthesis of psilocybin from glucose as well as 13 psilocybin derivatives from a library of derivatized indole substrates. This was made possible by the inclusion of a P450, PsiH, to the previously established biosynthetic pathway. Along the way, the authors were able to probe the substrate promiscuity and transcriptional sensitivity of the pathway enzymes in vivo.