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Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems
Alternative Title通过两种不同位点特异性重组系统遗传改造筑波链霉菌增加聚酮化合物独特衍生单元的前提供应以提高FK506的产量
Chen DD(陈单丹); Zhang Q(张琪); Zhang QL(张庆林); Cen PL(岑沛霖); Xu ZN(徐志南); Liu W(刘文)
2012
Source PublicationAppl. Environ. Microbiol.
ISSN0099-2240
Volume78Issue:15Pages:5093-5103
AbstractFK506 is a potent immunosuppressant that has a wide range of clinical applications. Its 23-member macrocyclic scaffold, mainly with a polyketide origin, features two methoxy groups at C-13 and C-15 and one allyl side chain at C-21, due to the region-specific incorporation of two unusual extender units derived from methoxymalonyl-acyl carrier protein (ACP) and allylmalonyl-coenzyme A (CoA), respectively. Whether their intracellular formations can be a bottleneck for FK506 production remains elusive. In this study, we report the improvement of FK506 yield in the producing strain Streptomyces tsukubaensis by the duplication of two sets of pathway-specific genes individually encoding the biosyntheses of these two extender units, thereby providing a promising approach to generate high-FK506-producing strains via genetic manipulation. Taking advantage of the fact that S. tsukubaensis is amenable to two actinophage (Phi C31 and VWB) integrase-mediated recombination systems, we genetically enhanced the biosyntheses of methoxymalonyl-ACP and allylmalonyl-CoA, as indicated by transcriptional analysis. Together with the optimization of glucose supplementation, the maximal FK506 titer eventually increased by approximately 150% in comparison with that of the original strain. The strategy of engineering the biosynthesis of unusual extender units described here may be applicable to improving the production of other polyketide or nonribosomal peptide natural products that contain pathway-specific building blocks.
Subject Area生命有机化学
Department浙江大学; 中科院上海有机化学研究所
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Indexed BySCI
Language英语
WOS IDWOS:000306532500008
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Document Type期刊论文
Identifierhttp://ir.sioc.ac.cn/handle/331003/28485
Collection生命有机化学国家重点实验室
Corresponding AuthorXu ZN(徐志南); Liu W(刘文)
Recommended Citation
GB/T 7714
Chen DD,Zhang Q,Zhang QL,et al. Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems[J]. Appl. Environ. Microbiol.,2012,78(15):5093-5103.
APA 陈单丹,张琪,张庆林,岑沛霖,徐志南,&刘文.(2012).Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems.Appl. Environ. Microbiol.,78(15),5093-5103.
MLA 陈单丹,et al."Improvement of FK506 Production in Streptomyces tsukubaensis by Genetic Enhancement of the Supply of Unusual Polyketide Extender Units via Utilization of Two Distinct Site-Specific Recombination Systems".Appl. Environ. Microbiol. 78.15(2012):5093-5103.
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