{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T16:52:28Z","timestamp":1770742348114,"version":"3.49.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2023,7,1]],"date-time":"2023-07-01T00:00:00Z","timestamp":1688169600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2021YFC2100600"],"award-info":[{"award-number":["2021YFC2100600"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2019YFA09005400"],"award-info":[{"award-number":["2019YFA09005400"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32170057"],"award-info":[{"award-number":["32170057"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,7,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Aims<\/jats:title>\n                  <jats:p>Study of the effect of isoleucine on the biosynthesis of FK506 and modification of its producing strain to improve the production of FK506.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods and Results<\/jats:title>\n                  <jats:p>Metabolomics analysis was conducted to explore key changes in the metabolic processes of Streptomyces tsukubaensis \u039468 in medium with and without isoleucine. In-depth analysis revealed that the shikimate pathway, methylmalonyl-CoA, and pyruvate might be the rate-limiting factors in FK506 biosynthesis. Overexpression of involved gene PCCB1 in S. tsukubaensis \u039468, a high-yielding strain \u039468-PCCB1 was generated. Additionally, the amino acids supplement was further optimized to improve FK506 biosynthesis. Finally, FK506 production was increased to 929.6\u2009mg\u2009L\u22121, which was 56.6% higher than that in the starter strain, when supplemented isoleucine and valine at 9 and 4\u2009g\u2009L\u22121, respectively.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Methylmalonyl-CoA might be the key rate-limiting factors in FK506 biosynthesis and overexpression of the gene PCCB1 and further addition of isoleucine and valine could increase the yield of FK506 by 56.6%.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jambio\/lxad142","type":"journal-article","created":{"date-parts":[[2023,7,9]],"date-time":"2023-07-09T12:00:50Z","timestamp":1688904050000},"source":"Crossref","is-referenced-by-count":4,"title":["Production improvement of FK506 in <i>Streptomyces tsukubaensis<\/i> by metabolic engineering strategy"],"prefix":"10.1093","volume":"134","author":[{"given":"Hai-Tao","family":"Chen","sequence":"first","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiao-Ying","family":"Zhang","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing-Bin","family":"Wu","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing-Wei","family":"Zhao","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin-Ai","family":"Chen","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yong-Quan","family":"Li","sequence":"additional","affiliation":[{"name":"First Affiliated Hospital and Institute of Pharmaceutical Biotechnology, Zhejiang University School of Medicine , Hangzhou 310058 , China"},{"name":"Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering , Hangzhou 310058 , China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,7,10]]},"reference":[{"key":"2023072414175462900_bib1","doi-asserted-by":"crossref","first-page":"4776","DOI":"10.1073\/pnas.1015773108","article-title":"Biosynthesis of the immunosuppressants FK506, FK520, and rapamycin involves a previously undescribed family of enzymes acting on chorismite","volume":"108","author":"Andexer","year":"2011","journal-title":"Proc Natl Acad Sci 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