ArticleApplied and environmental microbiology2012
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.
Article in Applied and environmental microbiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 67 citations in OpenAlex.
- Evaluation of vector system in Saccharopolyspora erythraea and construction of new replicative vector.Applied microbiology and biotechnology · 2026Article
- Enhancement of FK520 production in Streptomyces hygroscopicus var. ascomyceticus ATCC 14891 by overexpressing the regulatory gene fkbR2.Bioprocess and biosystems engineering · 2025Article
- An NADH/NADApplied and environmental microbiology · 2024Article
- Improved polyketide production in C. glutamicum by preventing propionate-induced growth inhibition.Nature metabolism · 2023Article
- Optimization of FK-506 production in Streptomyces tsukubaensis by modulation of Crp-mediated regulation.Applied microbiology and biotechnology · 2023Article
- Aquaporin 4 in Traumatic Brain Injury: From Molecular Pathways to Therapeutic Target.Neurochemical research · 2022Review
- Optimization of the precursor supply for an enhanced FK506 production inFrontiers in bioengineering and biotechnology · 2022Article
- Improvement of FK506 production via metabolic engineering-guided combinational strategies in Streptomyces tsukubaensis.Microbial cell factories · 2021Article
- Bioengineering of Anti-Inflammatory Natural Products.ChemMedChem · 2021Review
- More P450s Are Involved in Secondary Metabolite Biosynthesis inInternational journal of molecular sciences · 2020Article
- Evaluation of carbon:nitrogen ratio in semi-defined culture medium to tacrolimus biosynthesis byBiotechnology reports (Amsterdam, Netherlands) · 2020Article
- Article
- Unraveling Nutritional Regulation of Tacrolimus Biosynthesis inAntibiotics (Basel, Switzerland) · 2018Review
- Substrate Specificity of Acyltransferase Domains for Efficient Transfer of Acyl Groups.Frontiers in microbiology · 2018Article
- dRNA-seq transcriptional profiling of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis NRRL18488 and general analysis of the transcriptome.RNA biology · 2017Article
- Combining metabolomics and network analysis to improve tacrolimus production in Streptomyces tsukubaensis using different exogenous feedings.Journal of industrial microbiology & biotechnology · 2017Article
- Metabolic network model guided engineering ethylmalonyl-CoA pathway to improve ascomycin production in Streptomyces hygroscopicus var. ascomyceticus.Microbial cell factories · 2017Article
- FkbN and Tcs7 are pathway-specific regulators of the FK506 biosynthetic gene cluster in Streptomyces tsukubaensis L19.Journal of industrial microbiology & biotechnology · 2016Article
- The biosynthetic pathway of FK506 and its engineering: from past achievements to future prospects.Journal of industrial microbiology & biotechnology · 2016Review
- Heterologous Production of the Marine Myxobacterial Antibiotic Haliangicin and Its Unnatural Analogues Generated by Engineering of the Biochemical Pathway.Scientific reports · 2016Article
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 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.
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