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Title: Characterization of the biosynthetic gene cluster and shunt products yields insights into the biosynthesis of balmoralmycin
Authors: Ma, Guang-Lei
Xin, Lingyi
Liao, Yanghui
Chong, Zhi-Soon
Candra, Hartono
Pang, Li Mei
Lee, Sean Qiu En
Gakuubi, Martin Muthee
Ng, Siew Bee
Liang, Zhao-Xun
Keywords: Science::Chemistry
Science::Biological sciences
Issue Date: 2022
Source: Ma, G., Xin, L., Liao, Y., Chong, Z., Candra, H., Pang, L. M., Lee, S. Q. E., Gakuubi, M. M., Ng, S. B. & Liang, Z. (2022). Characterization of the biosynthetic gene cluster and shunt products yields insights into the biosynthesis of balmoralmycin. Applied and Environmental Microbiology, 88(23), e0120822-.
Project: T2EP30221-0029 
Journal: Applied and Environmental Microbiology 
Abstract: Angucyclines are a family of structurally diverse, aromatic polyketides with some members that exhibit potent bioactivity. Angucyclines have also attracted considerable attention due to the intriguing biosynthetic origins that underlie their structural complexity and diversity. Balmoralmycin (compound 1) represents a unique group of angucyclines that contain an angular benz[a]anthracene tetracyclic system, a characteristic C-glycosidic bond-linked deoxy-sugar (D-olivose), and an unsaturated fatty acid chain. In this study, we identified a Streptomyces strain that produces balmoralmycin and seven biosynthetically related coproducts (compounds 228). Four of the coproducts (compounds 528) are novel compounds that feature a highly oxygenated or fragmented lactone ring, and three of them (compounds 325) exhibited cytotoxicity against the human pancreatic cancer cell line MIA PaCa-2 with IC50 values ranging from 0.9 to 1.2 mg/mL. Genome sequencing and CRISPR/dCas9-assisted gene knockdown led to the identification of the ;43 kb balmoralmycin biosynthetic gene cluster (bal BGC). The bal BGC encodes a type II polyketide synthase (PKS) system for assembling the angucycline aglycone, six enzymes for generating the deoxysugar D-olivose, and a hybrid type II/III PKS system for synthesizing the 2,4-decadienoic acid chain. Based on the genetic and chemical information, we propose a mechanism for the biosynthesis of balmoralmycin and the shunt products. The chemical and genetic studies yielded insights into the biosynthetic origin of the structural diversity of angucyclines.
ISSN: 0099-2240
DOI: 10.1128/aem.01208-22
Schools: School of Biological Sciences 
Organisations: Singapore Institute of Food and Biotechnology Innovation, A*STAR
Rights: © 2022 American Society for Microbiology. All Rights Reserved. This paper was published in Applied and Environmental Microbiology and is made available with permission of American Society for Microbiology.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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