Ma Hong-Min, Zhou Qiang, Tang Yu-Min, Zhang Zhuan, Chen Yong-Sheng, He Hai-Yan, Pan Hai-Xue, Tang Man-Cheng, Gao Ju-Fang, Zhao Sheng-Yin, Igarashi Yasuhiro, Tang Gong-Li
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Chem Biol. 2013 Jun 20;20(6):796-805. doi: 10.1016/j.chembiol.2013.04.013.
Kosinostatin (KST), an antitumor antibiotic, features a pyrrolopyrrole moiety spirally jointed to a five-membered ring of an anthraquinone framework glycosylated with a γ-branched octose. By a combination of in silico analysis, genetic characterization, biochemical assay, and precursor feeding experiments, a biosynthetic pathway for KST was proposed, which revealed (1) the pyrrolopyrrole moiety originates from nicotinic acid and ribose, (2) the bicyclic amidine is constructed by a process similar to the tryptophan biosynthetic pathway, and (3) a discrete adenylation enzyme and a peptidyl carrier protein (PCP) are responsible for producing a PCP-tethered building block parallel to type II polyketide synthase (PKS) rather than for the PKS priming step by providing the starter unit. These findings provide an opportunity to further explore the inexplicable enzymatic logic that governs the formation of pyrrolopyrrole moiety and the spirocyclic skeleton.
科西诺他汀（KST）是一种抗肿瘤抗生素，其特征在于一个吡咯并吡咯部分与一个蒽醌骨架的五元环螺旋连接，该五元环被一个γ-分支的辛糖糖基化。通过计算机分析、基因表征、生化测定和前体喂养实验相结合的方法，提出了KST的生物合成途径，该途径揭示：（1）吡咯并吡咯部分源自烟酸和核糖；（2）双环脒是通过类似于色氨酸生物合成途径的过程构建的；（3）一种离散的腺苷化酶和一种肽基载体蛋白（PCP）负责产生与II型聚酮合酶（PKS）平行的PCP连接的结构单元，而不是通过提供起始单元来进行PKS引发步骤。这些发现为进一步探索控制吡咯并吡咯部分和螺环骨架形成的难以解释的酶促逻辑提供了机会。
