Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics.
Construction of an octosyl acid backbone catalyzed by a radical S-adenosylmethionine enzyme and a phosphatase in the biosynthesis of high-carbon sugar nucleoside antibiotics.
复制标题
高碳糖核苷抗生素生物合成中自由基S-腺苷甲硫氨酸酶和磷酸酶催化辛基酸骨架的构建
DOI：
10.1039/c6sc01826b
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发表时间：
2017-01-01
期刊：
影响因子：
8.4
通讯作者：
Xiao Y
中科院分区：
文献类型：
--
作者：
He N;Wu P;Lei Y;Xu B;Zhu X;Xu G;Gao Y;Qi J;Deng Z;Tang G;Chen W;Xiao Y
这项工作首次为辛基酸通过自由基和去磷酸化酶促反应的生物合成起源提供了重要的体外证据。独特的双环辛糖醛酸核苷包括依佐霉素、马拉雅霉素和辛糖基酸 (OA)。它们的结构特征是 OA，这是一种不寻常的 8 碳呋喃糖基核苷核心，被认为是多氧霉素和尼可霉素的前体。尽管这些核苷抗生素的生物活性众所周知，但 OA 的生物合成尚未阐明。在这里，我们报告了多抗素生物合成途径中的两个关键酶促步骤，导致将 OA 鉴定为关键中间体。我们的数据表明，该中间体是通过自由基 S-腺苷甲硫氨酸 (SAM) 酶 PolH 催化的自由基反应形成的，并使用 3'-烯醇丙酮尿苷 5'-单磷酸 (3'-EUMP) 作为底物。随后由磷酸酶 PolJ 催化的去磷酸化将所得辛基酸 5'-磷酸 (OAP) 转化为 OA。这些结果首次为 OA C8 主链的生物合成起源提供了重要的体外证据。
This work provides, for the first time, significant in vitro evidence for the biosynthetic origins of octosyl acid through free radical and dephosphorylation enzymatic reactions. Unique bicyclic octosyl uronic acid nucleosides include ezomycin, malayamycin, and octosyl acid (OA). They are structurally characterized by OA, an unusual 8-carbon furanosyl nucleoside core proposed to be the precursor to polyoxin and nikkomycin. Despite the well-known bioactivity of these nucleoside antibiotics, the biosynthesis of OA has not been elucidated yet. Here we report the two pivotal enzymatic steps in the polyoxin biosynthetic pathway leading to the identification of OA as a key intermediate. Our data suggest that this intermediate is formed via a free radical reaction catalyzed by the radical S-adenosylmethionine (SAM) enzyme, PolH, and using 3′-enolpyruvyl uridine 5′-monophosphate (3′-EUMP) as a substrate. Subsequent dephosphorylation catalyzed by phosphatase PolJ converts the resulting octosyl acid 5′-phosphate (OAP) to OA. These results provide, for the first time, significant in vitro evidence for the biosynthetic origins of the C8 backbone of OA.