Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases

文献类型： 外文期刊

第一作者： Kuhnert, Eric

作者： Kuhnert, Eric;Li, Yan;Lan, Nan;Yue, Qun;Chen, Li;An, Zhiqiang;Bills, Gerald F.;Kuhnert, Eric;Cox, Russell J.;Kuhnert, Eric;Cox, Russell J.;Li, Yan;Yue, Qun;Yokoyama, Kenichi

作者机构：

期刊名称：ENVIRONMENTAL MICROBIOLOGY （ 影响因子：5.491； 五年影响因子：6.438 ）

ISSN： 1462-2912

年卷期： 2018 年 20 卷 9 期

页码：

收录情况： SCI

摘要： Enfumafungin is a glycosylated fernene-type triterpenoid produced by the fungus Hormonema carpetanum. Its potent antifungal activity, mediated by its interaction with beta-1,3-glucan synthase and the fungal cell wall, has led to its development into the semi-synthetic clinical candidate, ibrexafungerp (=SCY-078). We report on the preliminary identification of the enfumafungin biosynthetic gene cluster (BGC) based on genome sequencing, phylogenetic reconstruction, gene disruption, and cDNA sequencing studies. Enfumafungin synthase (efuA) consists of a terpene cyclase domain (TC) fused to a glycosyltransferase (GT) domain and thus represents a novel multifunctional enzyme. Moreover, the TC domain bears a phylogenetic relationship to bacterial squalene-hopene cyclases (SHC) and includes a typical DXDD motif within the active centre suggesting that efuA evolved from SHCs. Phylogenetic reconstruction of the GT domain indicated that this portion of the fusion gene originated from fungal sterol GTs. Eleven genes flanking efuA are putatively involved in the biosynthesis, regulation, transport and self-resistance of enfumafungin and include an acetyltransferase, three P450 monooxygenases, a dehydrogenase, a desaturase and a reductase. A hypothetical scheme for enfumafungin assembly is proposed in which the E-ring is oxidatively cleaved to yield the four-ring system of enfumafungin. EfuA represents the first member of a widespread lineage of fungal SHCs.

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