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<p>Warkmycin (<b>1</b>), a type II polyketide with complex post-modifications, exhibits potent antitumor activity. Through genome mining and biosynthetic investigations, we identified 20 warkmycin derivatives, 17 of which are new. In this study, we have corrected the nomenclature of sugar A in the structure of warkmycin (<b>1</b>) to <i>α</i>-L-oleandrose. We disclose here the biosynthetic pathway of warkmycins with a special emphasis on the spatiotemporal order of post-tailoring steps. Four glycosyltransferases (War8, War7, War10, and War11) sequentially loaded four rare deoxysugar groups: <i>α</i>-L-oleandrose, <i>β</i>-D-olivose, <i>β</i>-D-olivomycose, and <i>β</i>-D-amicetose. Additionally, the cytochrome P450 enzyme War9 catalyzes <i>β</i>-hydroxylation, the acetyltransferase War21 performs sequentially dual <i>O</i>-acetylation, and the carbamoyltransferase War1 facilitates <i>α</i>-L-oleandrose carbamoylation to generate the final product warkmycin (<b>1</b>). <i>In vitro</i> enzyme reaction results showed that War9, War21, and War1 all have good catalytic activity and substrate promiscuity, which are of great value for the modification of complex molecules. Structure-activity relationship (SAR) studies demonstrated the essentiality of these enzymatic modifications for bioactivity. Notably, the intermediate warkmycin Q (<b>18</b>) exhibited superior antitumor activity. This work not only deciphers the complex enzymatic machinery governing polyketide diversification but also provides novel lead compounds for antitumor drug development and enzymatic tools for the engineering of natural products.</p>

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Biosynthesis of antitumor warkmycins reveals spatiotemporal order of the tailoring steps involving multiple glycosylation, hydroxylation, dual O-acetylation and carbamoylation

  • 期刊论文

  • 发表日期：

    2025年7月4日

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  • Yanqing Li,
  • Shuyi Wu,
  • Yidi Wang,
  • Xianhua Cai,
  • Hua Zhang,
  • Le Zhou,
  • Zhuo Shang,
  • Yucheng Gu,
  • Junying Ma,
  • Jianhua Ju

摘要

Warkmycin (1), a type II polyketide with complex post-modifications, exhibits potent antitumor activity. Through genome mining and biosynthetic investigations, we identified 20 warkmycin derivatives, 17 of which are new. In this study, we have corrected the nomenclature of sugar A in the structure of warkmycin (1) to α-L-oleandrose. We disclose here the biosynthetic pathway of warkmycins with a special emphasis on the spatiotemporal order of post-tailoring steps. Four glycosyltransferases (War8, War7, War10, and War11) sequentially loaded four rare deoxysugar groups: α-L-oleandrose, β-D-olivose, β-D-olivomycose, and β-D-amicetose. Additionally, the cytochrome P450 enzyme War9 catalyzes β-hydroxylation, the acetyltransferase War21 performs sequentially dual O-acetylation, and the carbamoyltransferase War1 facilitates α-L-oleandrose carbamoylation to generate the final product warkmycin (1). In vitro enzyme reaction results showed that War9, War21, and War1 all have good catalytic activity and substrate promiscuity, which are of great value for the modification of complex molecules. Structure-activity relationship (SAR) studies demonstrated the essentiality of these enzymatic modifications for bioactivity. Notably, the intermediate warkmycin Q (18) exhibited superior antitumor activity. This work not only deciphers the complex enzymatic machinery governing polyketide diversification but also provides novel lead compounds for antitumor drug development and enzymatic tools for the engineering of natural products.