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.

Applied and Environmental Microbiology
Dandan ChenWen Liu

Abstract

FK506 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 (ΦC31 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 w...Continue Reading

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Citations

Jun 20, 2013·Journal of Industrial Microbiology & Biotechnology·Di HuangXiaoqiang Jia
Oct 1, 2013·BioMed Research International·Amit Kumar ChaudharyJae Kyung Sohng
Oct 23, 2012·BMC Microbiology·Dušan GoranovičHrvoje Petković
Nov 26, 2013·Applied Microbiology and Biotechnology·Carlos Barreiro, Miriam Martínez-Castro
Sep 8, 2015·Journal of Industrial Microbiology & Biotechnology·Yeon Hee BanYeo Joon Yoon
Sep 16, 2015·Journal of Applied Microbiology·T BennurV Javdekar
Oct 21, 2016·Journal of Industrial Microbiology & Biotechnology·Xiao-Sheng ZhangYong-Quan Li
Oct 25, 2016·Biotechnology Letters·Li-Feng FuHui Jiang
Oct 7, 2017·Applied Microbiology and Biotechnology·María Ordóñez-RoblesAntonio Rodríguez-García
Aug 23, 2018·Frontiers in Microbiology·Jie-Jie ShenYong-Quan Li
Jul 11, 2020·International Journal of Molecular Sciences·Fanele Cabangile MnguniKhajamohiddin Syed
Nov 20, 2020·ChemMedChem·Lea WinandMarkus Nett
May 10, 2013·ACS Synthetic Biology·Anna LechnerBradley S Moore

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