The Research Center of Chiral Drugs, Innovation Research Institute of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China.
Org Lett. 2021 Mar 19;23(6):2342-2346. doi: 10.1021/acs.orglett.1c00485. Epub 2021 Mar 8.
Rifamycins have been clinically utilized against mycobacterial infections for more than 50 years; however, their biosynthesis has not been fully elucidated. Here, on the basis of gene deletions, enzyme assays, isotope labeling, and site-directed mutations, we found that a flavin-dependent monooxygenase encoded by a rifamycin biosynthetic gene cluster, Rif-Orf17, not only converted the naphthoquinone chromophore of rifamycin S into benzo-γ-pyrone but also linearized rifamycin SV through phenolic hydroxylation. Both oxidation routes lead to inactivation of rifamycins.
利福霉素类抗生素已经在临床上用于治疗分枝杆菌感染超过 50 年，但它们的生物合成途径尚未完全阐明。在此，我们基于基因缺失、酶活性测定、同位素标记和定点突变，发现 rifamycin 生物合成基因簇编码的黄素依赖单加氧酶 Rif-Orf17，不仅将利福霉素 S 的萘醌发色团转化为苯并-γ-吡喃酮，还通过酚羟基化使利福霉素 SV 线性化。这两种氧化途径都会导致利福霉素失活。
