Year: 2025
Type: article
Abstract: 1,2,4-Triazine ring is a scaffold widely found in biologically active compounds, but how nature makes it remains enigmatic. In this study, we unveil the complex enzymatic and nonenzymatic cascade reactions that assemble the 1,2,4-triazine moiety found in the structures of the natural products pseudoiodinine and toxoflavin. Through biochemical studies, isotope labeling, and the application of substrate analogues, we propose a plausible pathway for the 1,2,4-triazine assembly from a common precursor in riboflavin biosynthesis. This process involves four two-electron oxidation steps, C-N bond formation, decarboxylation, and the N-N bond forming step catalyzed by a metal-dependent WD40-repeat (WDR) protein. This study thus not only provides the first biocatalytic route for the 1,2,4-triazine assembly but also identifies a previously unrecognized catalytic role of a large WDR protein family.
DOI: 10.1021/jacs.4c18761
Authors: Yiyuan Cheng, Haoran Pang, Wenjun Zhang
Institution: University of California, Berkeley
Language: English
Subfield: Pharmacology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4408960661