Kong Rixiang, Liu Xuejiao, Su Chun, Ma Chunyan, Qiu Rongguo, Tang Li
Research Center for Molecular Medicine, Dalian University of Technology, Dalian 116024, China.
Chem Biol. 2013 Jan 24;20(1):45-54. doi: 10.1016/j.chembiol.2012.10.018.
Fostriecin is a unique phosphate monoester antibiotic that was isolated from Streptomyces pulveraceus as a protein phosphatase 2A (PP2A) and PP4A selective inhibitor. However, its biosynthetic mechanism remains to be elucidated. In this study, a 73 kb gene cluster encoding a six modular Type I polyketide synthases (PKS) and seven tailoring enzymes was identified by cosmid sequencing from the producer. The functions of two tailoring enzymes were characterized by gene disruption and an in vitro enzyme activity assay. Remarkably, the isolation of three malonylated fostriecin analogs from post-PKS gene knockout mutants indicated malonylated-polyketide formation could be a normal biosynthetic process in the formation of the unsaturated six-membered lactone in fostriecin. Based on this study, a comprehensive post-PKS modification mechanism for fostriecin biosynthesis was proposed.
福司曲星是一种独特的磷酸单酯抗生素，它是从粉状链霉菌中分离出来的，作为一种蛋白磷酸酶2A（PP2A）和PP4A选择性抑制剂。然而，其生物合成机制仍有待阐明。在本研究中，通过粘粒测序从产生菌中鉴定出一个73 kb的基因簇，该基因簇编码一个六模块的I型聚酮合酶（PKS）和七种修饰酶。通过基因敲除和体外酶活性测定对两种修饰酶的功能进行了表征。值得注意的是，从PKS后基因敲除突变体中分离出三种丙二酰化福司曲星类似物，这表明丙二酰化聚酮的形成可能是福司曲星中不饱和六元内酯形成过程中的正常生物合成过程。基于本研究，提出了福司曲星生物合成的全面的PKS后修饰机制。
