Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
J Am Chem Soc. 2013 Feb 6;135(5):1735-8. doi: 10.1021/ja4001823. Epub 2013 Jan 28.
Iterative polyketide synthases (PKSs) are large, multifunctional enzymes that resemble eukaryotic fatty acid synthases but can make highly functionalized secondary metabolites using complex and unresolved programming rules. During biosynthesis of the kinase inhibitor hypothemycin by Hypomyces subiculosus , a highly reducing iterative PKS, Hpm8, cooperates with a nonreducing iterative PKS, Hpm3, to construct the advanced intermediate dehydrozearalenol (DHZ). The identity of putative intermediates in the formation of the highly reduced hexaketide portion of DHZ were confirmed by incorporation of (13)C-labeled N-acetylcysteamine (SNAC) thioesters using the purified enzymes. The results show that Hpm8 can accept SNAC thioesters of intermediates that are ready for transfer from its acyl carrier protein domain to its ketosynthase domain and assemble them into DHZ in cooperation with Hpm3. Addition of certain structurally modified analogues of intermediates to Hpm8 and Hpm3 can produce DHZ derivatives.
迭代聚酮合酶（PKSs）是大型多功能酶，类似于真核脂肪酸合酶，但可以使用复杂且未解决的编程规则来制造高度功能化的次生代谢物。在 Hypomyces subiculosus 产生激酶抑制剂 Hypothemycin 的过程中，高度还原的迭代 PKS Hpm8 与非还原的迭代 PKS Hpm3 合作构建了高级中间体去氢玉米赤霉醇（DHZ）。通过使用纯化的酶掺入（13）C 标记的 N-乙酰半胱氨酸（SNAC）硫酯，确认了 DHZ 中高度还原的六酮部分形成过程中假定中间体的身份。结果表明，Hpm8 可以接受来自其酰基载体蛋白结构域到酮合酶结构域的准备转移的中间体的 SNAC 硫酯，并与 Hpm3 合作将其组装成 DHZ。向 Hpm8 和 Hpm3 添加某些结构修饰的中间体类似物可以产生 DHZ 衍生物。
