Genomics-driven discovery of a biosynthetic gene cluster required for the synthesis of BII-Rafflesfungin from the fungus Phoma sp. F3723

Genomics-driven discovery of a biosynthetic gene cluster required for the synthesis of BII-Rafflesfungin from the fungus Phoma sp. F3723

Background: Phomafungin is a recently reported broad spectrum antifungal compound but its biosynthetic pathway is unknown. We combed publicly available Phoma genomes but failed to find any putative biosynthetic gene cluster that could account for its biosynthesis. Results: Therefore, we sequenced th...

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Bibliographic Details
Main Authors: Sinha, Swati, Nge, Choy-Eng, Leong, Chung Yan, Ng, Veronica, Crasta, Sharon, Goh, Falicia, Low, Kia-Ngee, Zhang, Huibin, Arumugam, Prakash, Lezhava, Alexander, Chen, Swaine L., Kanagasundaram, Yoganathan, Ng, Siew Bee, Eisenhaber, Frank, Eisenhaber, Birgit, Mohammad Alfatah
Other Authors: School of Computer Science and Engineering
Format: Article
Language:English
Published: 2019
Subjects:
DRNTU::Engineering::Computer science and engineering
Cyclic Lipodepsipeptide
Biosynthetic Gene Cluster
Online Access:https://hdl.handle.net/10356/105745
http://hdl.handle.net/10220/48736
http://dx.doi.org/10.1186/s12864-019-5762-6
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Institution: Nanyang Technological University
Language: English
Description
Summary:Background: Phomafungin is a recently reported broad spectrum antifungal compound but its biosynthetic pathway is unknown. We combed publicly available Phoma genomes but failed to find any putative biosynthetic gene cluster that could account for its biosynthesis. Results: Therefore, we sequenced the genome of one of our Phoma strains (F3723) previously identified as having antifungal activity in a high-throughput screen. We found a biosynthetic gene cluster that was predicted to synthesize a cyclic lipodepsipeptide that differs in the amino acid composition compared to Phomafungin. Antifungal activity guided isolation yielded a new compound, BII-Rafflesfungin, the structure of which was determined. Conclusions: We describe the NRPS-t1PKS cluster ‘BIIRfg’ compatible with the synthesis of the cyclic lipodepsipeptide BII-Rafflesfungin [HMHDA-L-Ala-L-Glu-L-Asn-L-Ser-L-Ser-D-Ser-D-allo-Thr-Gly]. We report new Stachelhaus codes for Ala, Glu, Asn, Ser, Thr, and Gly. We propose a mechanism for BII-Rafflesfungin biosynthesis, which involves the formation of the lipid part by BIIRfg_PKS followed by activation and transfer of the lipid chain by a predicted AMP-ligase on to the first PCP domain of the BIIRfg_NRPS gene.

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