This research was financially supported by the Pew Scholars Program and a UC Berkeley Faculty Research Grant. We thank M. Chang (UC Berkeley) for providing a protein-expression plasmid, J. Pelton (UC Berkeley) for assisting with NMR spectroscopic analysis, and J. Skerker (UC Berkeley) for helping with genome assembly.
Unusual Acetylation-Dependent Reaction Cascade in the Biosynthesis of the Pyrroloindole Drug Physostigmine†
Article first published online: 13 NOV 2013
Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Volume 126, Issue 1, pages 140–143, January 3, 2014
How to Cite
Liu, J., Ng, T., Rui, Z., Ad, O. and Zhang, W. (2014), Unusual Acetylation-Dependent Reaction Cascade in the Biosynthesis of the Pyrroloindole Drug Physostigmine. Angew. Chem., 126: 140–143. doi: 10.1002/ange.201308069
- Issue published online: 23 DEC 2013
- Article first published online: 13 NOV 2013
- Manuscript Received: 13 SEP 2013
- Pew Scholars Program
- UC Berkeley Faculty Research Grant
Physostigmine is a parasympathomimetic drug used to treat a variety of neurological disorders, including Alzheimer’s disease and glaucoma. Because of its potent biological activity and unique pyrroloindole skeleton, physostigmine has been the target of many organic syntheses. However, the biosynthesis of physostigmine has been relatively understudied. In this study, we identified a biosynthetic gene cluster for physostigmine by genome mining. The 8.5 kb gene cluster encodes eight proteins (PsmA–H), seven of which are required for the synthesis of physostigmine from 5-hydroxytryptophan, as shown by in vitro total reconstitution. Further genetic and enzymatic studies enabled us to delineate the biosynthetic pathway for physostigmine. The pathway features an unusual reaction cascade consisting of highly coordinated methylation and acetylation/deacetylation reactions.