Oxazolomycin Biosynthesis in Streptomyces albus JA3453 Featuring an “Acyltransferase-less” Type I Polyketide Synthase That Incorporates Two Distinct Extender Units*
Oxazolomycin Biosynthesis in Streptomyces albus JA3453 Featuring an “Acyltransferase-less” Type I Polyketide Synthase That Incorporates Two Distinct Extender Units*
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DOI：
10.1074/jbc.m109.090092
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发表时间：
2010-04
期刊：
影响因子：
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通讯作者：
Chunhua Zhao;J. Coughlin;J. Ju;Dongqing Zhu;E. Wendt-Pienkowski;Xiu-fen Zhou;Zhijun Wang;B. She
中科院分区：
文献类型：
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作者：
Chunhua Zhao;J. Coughlin;J. Ju;Dongqing Zhu;E. Wendt-Pienkowski;Xiu-fen Zhou;Zhijun Wang;B. She
恶唑霉素（oxazolomycins，OZMs）是由几种链霉菌产生的抗生素家族，其显示出多样且重要的抗菌、抗肿瘤和抗人类免疫缺陷病毒活性。恶唑霉素A是一种肽-聚酮杂合化合物，含有独特的螺连接的β-内酯/γ-内酰胺，即5-取代恶唑环。从白色链霉菌JA 3453中鉴定出恶唑霉素生物合成基因簇（ozm），定位于79.5-kb DNA，由20个开放阅读框组成，编码非核糖体肽脱氢酶、聚酮脱氢酶（PKS）、杂合非核糖体肽脱氢酶-PKS、转酰基转移酶（trans-AT）、用于甲氧丙二酰-酰基载体蛋白（ACP）合成的酶、推定的抗性基因和假设的调控基因。与经典的I型聚酮或脂肪酸生物酶相反，基因簇中的所有10个PKS模块都缺乏同源AT。相反，配备离散AT OzmM（具有串联结构域OzmM-AT 1和OzmM-AT 2）和OzmC以执行丙二酰-CoA和甲氧基丙二酰-ACP延伸物单元两者的所有加载功能。引人注目的是，OzmM-AT 2是OzmM生物合成活性所需的，而OzmM-AT 1似乎是一个隐藏的AT结构域。上述研究结果，连同以前的结果，使用同位素标记的前体喂养测定，组装的OZM生物合成模型提出。丙二酰-CoA（通过OzmM-AT 2）和甲氧基丙二酰-ACP（通过OzmC）延伸单元的掺入对于这类trans-AT I型PKS似乎是前所未有的，其可以被有效地操纵以产生结构多样的新型化合物。
The oxazolomycins (OZMs) are a growing family of antibiotics produced by several Streptomyces species that show diverse and important antibacterial, antitumor, and anti-human immunodeficiency virus activity. Oxazolomycin A is a peptide-polyketide hybrid compound containing a unique spiro-linked β-lactone/γ-lactam, a 5-substituted oxazole ring. The oxazolomycin biosynthetic gene cluster (ozm) was identified from Streptomyces albus JA3453 and localized to 79.5-kb DNA, consisting of 20 open reading frames that encode non-ribosomal peptide synthases, polyketide synthases (PKSs), hybrid non-ribosomal peptide synthase-PKS, trans-acyltransferases (trans-ATs), enzymes for methoxymalonyl-acyl carrier protein (ACP) synthesis, putative resistance genes, and hypothetical regulation genes. In contrast to classical type I polyketide or fatty acid biosynthases, all 10 PKS modules in the gene cluster lack cognate ATs. Instead, discrete ATs OzmM (with tandem domains OzmM-AT1 and OzmM-AT2) and OzmC were equipped to carry out all of the loading functions of both malonyl-CoA and methoxymalonyl-ACP extender units. Strikingly, only OzmM-AT2 is required for OzmM activity for OZM biosynthesis, whereas OzmM-AT1 seemed to be a cryptic AT domain. The above findings, together with previous results using isotope-labeled precursor feeding assays, are assembled for the OZM biosynthesis model to be proposed. The incorporation of both malonyl-CoA (by OzmM-AT2) and methoxymalonyl-ACP (by OzmC) extender units seemed to be unprecedented for this class of trans-AT type I PKSs, which might be fruitfully manipulated to create structurally diverse novel compounds.