Department of Chemistry, Duke University, Durham, North Carolina 27710, United States.
Department of Biochemistry, Duke University, Durham, North Carolina 27710, United States.
ACS Chem Biol. 2022 Apr 15;17(4):898-907. doi: 10.1021/acschembio.1c00971. Epub 2022 Mar 29.
Establishing a general biosynthetic scheme for natural products is critical for a broader understanding of natural product biosynthesis and the structural prediction of metabolites based on genome sequence information. High-carbon sugar nucleoside antimicrobials are an underexplored class of natural products with unique structures and important biological activities. Recent studies on C6 sugar nucleoside antifungal natural products, such as nikkomycins and polyoxins, revealed a novel biosynthetic mechanism involving cryptic phosphorylation. However, the generality of this biosynthetic mechanism remained unexplored. We here report in vitro characterization of the biosynthesis of a C7 sugar nucleoside antifungal, malayamycin A. Our results demonstrate that the malayamycin biosynthetic enzymes specifically accept 2'-phosphorylated biosynthetic intermediates, suggesting that cryptic phosphorylation-mediated biosynthesis is conserved beyond C6 sugar nucleosides. Furthermore, the results suggest a generalizable divergent biosynthetic mechanism for high-carbon sugar nucleoside antifungals. In this model, C6 and C7 sugar nucleoside biosyntheses proceed via a common C8 sugar nucleoside precursor, and the sugar size is determined using the functions of α-ketoglutarate (α-KG)-dependent dioxygenases (NikI/PolD for C6 sugar nucleosides and MalI for C7 sugar nucleosides). These results provide an important guidance for the future genome-mining discovery of high-carbon sugar nucleoside antimicrobials.
建立天然产物的一般生物合成方案对于更广泛地理解天然产物生物合成以及基于基因组序列信息对代谢物进行结构预测至关重要。高碳糖核苷类抗生素是一类尚未充分研究的天然产物，具有独特的结构和重要的生物活性。最近对 C6 糖核苷类抗真菌天然产物（如 nikkomycins 和 polyoxins）的研究揭示了一种涉及隐匿磷酸化的新型生物合成机制。然而，这种生物合成机制的普遍性仍未得到探索。我们在这里报道了 C7 糖核苷类抗真菌物质 malayamycin A 的生物合成的体外特征。我们的结果表明，malayamycin 生物合成酶特异性地接受 2'-磷酸化的生物合成中间体，这表明隐匿磷酸化介导的生物合成在 C6 糖核苷之外是保守的。此外，这些结果表明了高碳糖核苷类抗生素的一种可推广的发散生物合成机制。在该模型中，C6 和 C7 糖核苷生物合成通过一个共同的 C8 糖核苷前体进行，并且使用α-酮戊二酸（α-KG）依赖性双加氧酶（NikI/PolD 用于 C6 糖核苷和 MalI 用于 C7 糖核苷）的功能来确定糖的大小。这些结果为未来通过基因组挖掘发现高碳糖核苷类抗生素提供了重要指导。
