Mori Shogo, Simkhada Dinesh, Zhang Huitu, Erb Megan S, Zhang Yang, Williams Howard, Fedoseyenko Dmytro, Russell William K, Kim Doyong, Fleer Nathan, Ealick Steven E, Watanabe Coran M H
Department of Chemistry, Texas A&M University , College Station, Texas 77843, United States.
Department of Chemistry and Chemical Biology, Cornell University , Ithaca, New York 14853, United States.
Biochemistry. 2016 Feb 2;55(4):704-14. doi: 10.1021/acs.biochem.5b01050. Epub 2016 Jan 19.
The azinomycins are a family of potent antitumor agents with the ability to form interstrand cross-links 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.
氮霉素是一类具有与DNA形成链间交联能力的强效抗肿瘤药物。本研究报道了对有效DNA结合至关重要的5-甲基萘甲酸部分的异常生物合成形成。虽然序列分析预测聚酮合酶(AziB)催化该萘甲酸的形成,但却形成了截短的单环产物2-甲基苯甲酸。我们证明硫酯酶(AziG)作为链延伸和环化(CEC)结构域,是形成预期产物所需的额外两轮链延伸所必需的。