Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases.
Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases.
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DOI：
10.1111/1462-2920.14333
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发表时间：
2018-09
影响因子：
5.1
通讯作者：
Bills GF
中科院分区：
文献类型：
--
作者：
Kuhnert E;Li Y;Lan N;Yue Q;Chen L;Cox RJ;An Z;Yokoyama K;Bills GF
Enfumafungin是由真菌Hormonema carpetanum产生的一种糖基化的二烯类三萜类化合物。通过与β−1，3-葡聚糖合成酶和真菌细胞壁的相互作用，其强大的抗真菌活性使其发展成为半合成的临床候选药物ibrexafungerp。我们报道了基于基因组测序、系统发育重建、基因破坏和cDNA测序研究的Enfumafungin生物合成基因簇(BGC)的初步鉴定。Enfumafungin合成酶(EfuA)由一个萜烯环酶结构域(TC)和一个糖基转移酶(GT)结构域组成，是一种新型的多功能酶。此外，TC结构域与细菌角鲨烯-Hopene环酶(SHC)具有系统发育关系，并在活性中心包含一个典型的DXDD基序，表明EfuA是从SHCS进化而来的。GT结构域的系统发育重建表明，该融合基因来源于真菌甾醇GTS。EfuA两侧的11个基因可能参与了Enfumafungin的生物合成、调节、运输和自身抗性，包括一个乙酰转移酶、三个P450单加氧酶、一个脱氢酶、一个去饱和酶和一个还原酶。提出了一种假想的Enfumafungin组装方案，其中E环被氧化裂解，生成Enfumafungin的四环体系。EfuA代表了广泛存在的真菌SHC谱系中的第一个成员。
Enfumafungin is a glycosylated fernene-type triterpenoid produced by the fungus Hormonema carpetanum. Its potent antifungal activity, mediated by its interaction with β−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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影响因子：
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作者：
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