Biosynthesis mechanism, genome mining and artificial construction of echinocandin O-sulfonation
Biosynthesis mechanism, genome mining and artificial construction of echinocandin O-sulfonation
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DOI：
10.1016/j.ymben.2022.10.006
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发表时间：
2022-11-01
影响因子：
8.4
通讯作者：
Lu, Xuefeng
中科院分区：
文献类型：
--
作者：
Men, Ping;Geng, Ce;Lu, Xuefeng
米卡芬净是由Coleophoma empetri发酵产生的环状六肽FR 901379的半合成衍生物，是唯一的O-磺酸化棘白菌素型抗真菌药物。然而，O-磺酸基的详细形成机制，无论是在六肽组装之前还是之后，仍然难以捉摸。在这里，我们证实了O-磺酰化发生在六肽组装后，作为一种后修饰在FR 901379的生物合成。释放的环六肽被细胞色素P450 McfP羟基化，并被磺基转移酶McfS连续磺化。以McfS为序列探针，通过基因组挖掘，鉴定了另外3种棘白菌素磺基转移酶。此外，卡泊芬净的前体肺炎球菌素B-0可通过将McfP-McfS异源引入肺炎球菌素B-0产生菌Glarea lozoyensis中而O-磺化。磺化肺炎白菌素B-0的水溶性是肺炎白菌素B-0的4000倍。揭示的O-磺化机理将为通过代谢工程设计和生产新型磺化棘白菌素提供新的见解。
Micafungin, a semisynthetic derivative of the cyclic hexapeptide FR901379 produced by Coleophoma empetri fermentation, is the only O-sulfonated echinocandin-type antifungal drug. However, the detailed formation mechanism of O-sulfonate group, whether before or after the assembly of hexapeptide, remains elusive. Here, we confirmed that O-sulfonylation occurs after hexapeptide assembly as a kind of postmodification in the biosynthesis of FR901379. The released cyclic hexapeptide was hydroxylated by cytochrome P450 McfP and successively sulfonated by sulfotransferase McfS. And other three echinocandin sulfotransferases were identified through genome mining by using McfS as a sequence probe. Moreover, pneumocandin B-0, the precursor of caspofungin, could be O-sulfonated by heterologously introducing the McfP-McfS into the pneumocandin B-0-producing species Glarea lozoyensis. The water-solubility of sulfonated pneumocandin B-0 is 4000 times higher than that of pneumocandin B-0. The revealed O-sulfonation mechanism will provide new insights into the design and production of novel sulfonated echinocandins by metabolic engineering.