Details
| Original language | English |
|---|---|
| Pages (from-to) | 3325-3342 |
| Number of pages | 18 |
| Journal | Environmental microbiology |
| Volume | 20 |
| Issue number | 9 |
| Early online date | 26 Jul 2018 |
| Publication status | Published - 27 Sept 2018 |
Abstract
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.
ASJC Scopus subject areas
- Immunology and Microbiology(all)
- Microbiology
- Agricultural and Biological Sciences(all)
- Ecology, Evolution, Behavior and Systematics
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In: Environmental microbiology, Vol. 20, No. 9, 27.09.2018, p. 3325-3342.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - Enfumafungin synthase represents a novel lineage of fungal triterpene cyclases
AU - Kuhnert, Eric
AU - Li, Yan
AU - Lan, Nan
AU - Yue, Qun
AU - Chen, Li
AU - Cox, Russell J.
AU - An, Zhiqiang
AU - Yokoyama, Kenichi
AU - Bills, Gerald F.
N1 - Funding information: EK’s work at the University of Texas Health Science Centre at Houston was supported by a German Academic Exchange Service (DAAD) Postdoctoral Fellowship. In addition, work was supported by a Robert Welch Foundation Grant AU-20030616 (to ZA), the University of Texas Health Science Centre at Houston new faculty start-up funds, the Kay and Ben Fortson Endowment, and the National Institute of General Medical Sciences R01GM121458 (to GB). KY was supported by the Duke University Medical Center and the National Institute of General Medical Sciences R01GM115729. RJC thanks the Deutsche Forschungsge-meinschaft for LCMS equipment (INST 187/621). EK's work at the University of Texas Health Science Centre at Houston was supported by a German Academic Exchange Service (DAAD) Postdoctoral Fellowship. In addition, work was supported by a Robert Welch Foundation Grant AU-20030616 (to ZA), the University of Texas Health Science Centre at Houston new faculty start-up funds, the Kay and Ben Fortson Endowment, and the National Institute of General Medical Sciences R01GM121458 (to GB). KY was supported by the Duke University Medical Center and the National Institute of General Medical Sciences R01GM115729. RJC thanks the Deutsche Forschungsgemeinschaft for LCMS equipment (INST 187/621).
PY - 2018/9/27
Y1 - 2018/9/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85053384350&partnerID=8YFLogxK
U2 - 10.1111/1462-2920.14333
DO - 10.1111/1462-2920.14333
M3 - Article
C2 - 30051576
AN - SCOPUS:85053384350
VL - 20
SP - 3325
EP - 3342
JO - Environmental microbiology
JF - Environmental microbiology
SN - 1462-2912
IS - 9
ER -