Steve Ealick's Research Group

Abstract:

Mori S, Simkhada D, Zhang H, Erb MS, Zhang Y, Williams HJ, Fedoseyenko D, Russell WK, Kim D, Fleer N, Ealick SE, and Watanabe CM. Polyketide Ring Expansion Mediated by a Thioesterase, CEC Domain, in Azinomycin Biosynthesis: Characterization of AziB and AziG. Biochemistry 55:704-714 (2016).

The azinomycins are a family of potent anti-tumor agents with the ability to form interstrand crosslinks with DNA. This study reports on the unusual biosynthetic formation of the 5-methyl naphthoate moiety, which is essential for effective DNA association. While sequence analysis predicts that the polyketide synthase (AziB) catalyzes the formation of this naphthoate, 2-methylbenzoic acid, a truncated single-ring product, is formed instead. We demonstrate that the thioesterase (AziG) acts as a chain elongation and cyclization (CEC) domain and is required for the additional two rounds of chain extension to form the expected product.