Pyrazofurin Biosynthesis Involves Nonenzymatic Ring Contraction of a Pyridazine Intermediate Triggered by a Rieske Enzyme-Catalyzed Oxygenation.

ABSTRACT: Pyrazofurin and formycin A are two pyrazole-containing C-nucleosides, exhibiting antibacterial, antiviral, and antitumor activities. Despite previous studies elucidating the early biosynthetic steps of pyrazole formation, how the linear hydrazone intermediate is cyclized to a pyrazole ring remains unknown. Herein, substrate analogs are used to show that the amidohydrolase PyfA mediates intramolecular cyclization of 2-hydrazinylidenepentanedioic acid to yield a 4,5-dihydropyridazine ring, which can undergo PyfO-catalyzed dehydrogenation to generate a pyridazine product. More importantly, the Rieske enzyme PyfB is demonstrated to catalyze oxygenation of 4,6-dihydroxypyridazine-3-carboxylic acid. The resulting six-membered pyridazine product is found to undergo uncatalyzed rearrangemen

SUBMITTER: Zheng Z 

PROVIDER: S-EPMC12857792 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature