Isolation of the biosynthetic gene cluster for tautomycetin, a linear polyketide T cell-specific immunomodulator from Streptomyces sp CK4412
Isolation of the biosynthetic gene cluster for tautomycetin, a linear polyketide T cell-specific immunomodulator from Streptomyces sp CK4412
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DOI：
10.1099/mic.0.2006/003194-0
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发表时间：
2007-04-01
期刊：
影响因子：
2.8
通讯作者：
Kim, Eung-Soo
中科院分区：
文献类型：
--
作者：
Choi, Si-Sun;Hur, Yoon-Ah;Kim, Eung-Soo
链霉菌（Streptomyces）细菌属因其能够产生各种医学上重要的次级代谢物，如抗生素、抗肿瘤剂、免疫抑制剂和酶抑制剂而长期受到重视。Tautomycetin （TMC）是由链霉菌（Streptomyces sp. CK4412）产生的一种新型活化的T细胞特异性免疫抑制化合物，其末端环酸酐片段与带有不寻常末端烯烃的线性聚酮链之间存在酯键连接。以链霉菌聚酮甲基丙二酰辅酶a酰基转移酶基因为探针，从产tmc链霉菌CK4412基因组文库中分离到3个重叠的子体。大约70 kb的连续DNA区域的序列信息显示了两个多模块I型聚酮合成酶（pks），以及12个可能参与TMC生物合成的额外基因产物。大多数TMC PKS催化结构域的作用与TMC链延伸和加工所需的预期功能一致。此外，位于PKS基因位点上游的一个假定的TMC酰基辅酶a转移酶基因的破坏，完全破坏了TMC的生物合成。综上所述，这些数据提供了强有力的支持证据，证明本研究中鉴定的克隆基因簇负责链霉菌CK4412中TMC的生物合成，并为这一重要代谢物的生物合成的详细遗传和生化研究奠定了基础。
The bacterial genus Streptomyces has long been appreciated for its ability to produce various kinds of medically important secondary metabolites, such as antibiotics, anti-tumour agents, immunosuppressants and enzyme inhibitors. Tautomycetin (TMC), which is produced by Streptomyces sp. CK4412, is a novel activated T cell-specific immunosuppressive compound with an ester bond linkage between a terminal cyclic anhydride moiety and a linear polyketide chain bearing an unusual terminal alkene. Using a Streptomyces polyketide methylmalonyl-CoA acyltransferase gene as a probe, three overlapping cosmids were isolated from the genomic library of TMC-producing Streptomyces sp. CK4412. Sequence information of an approximately 70 kb contiguous DNA region revealed two multi-modular type I polyketide synthases (PKSs), and 12 additional gene products presumably involved in TMC biosynthesis. The deduced roles for most of the TMC PKS catalytic domains were consistent with the expected functions necessary for TMC chain elongation and processing. In addition, disruption of a putative TMC acyl-CoA transferase gene, located upstream of the PKS gene locus, completely abolished TMC biosynthesis. Taken together, these data provide strong supporting evidence that the cloned gene cluster identified in this study is responsible for TMC biosynthesis in Streptomyces sp. CK4412, and set the stage for detailed genetic and biochemical studies of the biosynthesis of this important metabolite.