Unveiling sequential late-stage methyltransferase reactions in the meleagrin/oxaline biosynthetic pathway

Organic & Biomolecular Chemistry
Sean A NewmisterDavid H Sherman

Abstract

Antimicrobial and anti-proliferative meleagrin and oxaline are roquefortine C-derived alkaloids produced by fungi of the genus Penicillium. Tandem O-methylations complete the biosynthesis of oxaline from glandicoline B through meleagrin. Currently, little is known about the role of these methylation patterns in the bioactivity profile of meleagrin and oxaline. To establish the structural and mechanistic basis of methylation in these pathways, crystal structures were determined for two late-stage methyltransferases in the oxaline and meleagrin gene clusters from Penicillium oxalicum and Penicillium chrysogenum. The homologous enzymes OxaG and RoqN were shown to catalyze penultimate hydroxylamine O-methylation to generate meleagrin in vitro. Crystal structures of these enzymes in the presence of methyl donor S-adenosylmethionine revealed an open active site, which lacks an apparent base indicating that catalysis is driven by proximity effects. OxaC was shown to methylate meleagrin to form oxaline in vitro, the terminal pathway product. Crystal structures of OxaC in a pseudo-Michaelis complex containing sinefungin and meleagrin, and in a product complex containing S-adenosyl-homocysteine and oxaline, reveal key active site residue...Continue Reading

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Citations

Apr 13, 2019·FEMS Microbiology Ecology·Alvaro Salinero-LanzaroteLuis Rey
Jun 1, 2019·Signal Transduction and Targeted Therapy·Qiu SunWei Cheng
May 24, 2020·Signal Transduction and Targeted Therapy·Qiu SunWei Cheng
Mar 30, 2021·Acta Pharmaceutica Sinica. B·Qiu SunYuquan Wei
Apr 10, 2021·International Journal of Biological Macromolecules·Gangming Xu, Suiqun Yang
Aug 7, 2019·Journal of Chemical Theory and Computation·Susanta DasDan T Major

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Datasets Mentioned

BETA
GM118101

Methods Mentioned

BETA
NMR
co-crystallization

Software Mentioned

Molrep
CCP4
Autodock VINA
Refmac
Coot
XDS
Phenix
MCSG Suite
GraphPad Prism
DALI

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