Zhao Houyuan, Bu Junling, Liu Hung-Wen
Department of Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
Division of Chemical Biology and Medicinal Chemistry, University of Texas at Austin, Austin, Texas 78712, United States.
J Am Chem Soc. 2025 Feb 5;147(5):4180-4187. doi: 10.1021/jacs.4c13760. Epub 2025 Jan 24.
Mycobacidin is an antitubercular antibiotic structurally composed of a sulfur-containing 4-thiazolidinone ring, yet its biosynthesis including the mechanism of sulfur incorporation has remained an open question since its discovery in 1952. In this study, the mycobacidin biosynthetic gene cluster is identified from soil-dwelling , and the corresponding biosynthetic pathway starting with 7-oxoheptanoate is characterized. The radical SAM enzyme MybB catalyzes two sulfur insertion reactions, thereby bridging C and C to complete the 4-thiazolidinone heterocycle as the final step in mycobacidin maturation. MybB is a homologue of biotin synthase, and in both biosynthetic pathways, the bridging sulfur originates from the degradation of an enzymatic auxiliary [FeS] cluster. Introduction of the two C-S bonds during 4-thiazolidinone cyclization is shown to take place in a fixed sequence with the terminal C-S bond generated first followed by the C-S bond. MybB thus represents a generalization of biotin synthase activity that contributes to the maturation of not only primary but also secondary metabolites via sequential sulfur insertion reactions to yield sulfur containing heterocycles.
分枝杆菌酸是一种抗结核抗生素，其结构由一个含硫的4-噻唑烷酮环组成，然而自1952年发现以来，其生物合成，包括硫掺入的机制一直是个未解之谜。在本研究中，从土壤中鉴定出分枝杆菌酸生物合成基因簇，并对以7-氧代庚酸为起始物的相应生物合成途径进行了表征。自由基S-腺苷甲硫氨酸酶MybB催化两个硫插入反应，从而连接C和C以完成4-噻唑烷酮杂环的合成，这是分枝杆菌酸成熟的最后一步。MybB是生物素合酶的同源物，在这两种生物合成途径中，桥连硫均源自一种酶辅助[FeS]簇的降解。4-噻唑烷酮环化过程中两个C-S键的引入显示是以固定顺序发生的，首先生成末端C-S键，随后是C-S键。因此，MybB代表了生物素合酶活性的一种普遍化，它不仅通过顺序硫插入反应促进初级代谢产物的成熟，还促进次级代谢产物的成熟，以产生含硫杂环。
