The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family
Heinilä, L. M. P., Fewer, D. P., Jokela, J. K., Wahlsten, M., Ouyang, X., Permi, P., Jortikka, A., & Sivonen, K. (2021). The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family. Organic and Biomolecular Chemistry, 19(25), 5577-5588. https://doi.org/10.1039/D1OB00772F
Published inOrganic and Biomolecular Chemistry
© 2021 The Royal Society of Chemistry
Laxaphycins are a family of cyclic lipopeptides with synergistic antifungal and antiproliferative activities. They are produced by multiple cyanobacterial genera and comprise two sets of structurally unrelated 11- and 12-residue macrocyclic lipopeptides. Here, we report the discovery of new antifungal laxaphycins from Nostoc sp. UHCC 0702, which we name heinamides, through antimicrobial bioactivity screening. We characterized the chemical structures of eight heinamide structural variants A1–A3 and B1–B5. These variants contain the rare non-proteinogenic amino acids 3-hydroxy-4-methylproline, 4-hydroxyproline, 3-hydroxy-D-leucine, dehydrobutyrine, 5-hydroxyl β-amino octanoic acid, and O-carbamoyl-homoserine. We obtained an 8.6-Mb complete genome sequence from Nostoc sp. UHCC 0702 and identified the 93 kb heinamide biosynthetic gene cluster. The structurally distinct heinamides A1–A3 and B1–B5 variants are synthesized using an unusual branching biosynthetic pathway. The heinamide biosynthetic pathway also encodes several enzymes that supply non-proteinogenic amino acids to the heinamide synthetase. Through heterologous expression, we showed that (2S,4R)-4-hydroxy-L-proline is supplied through the action of a novel enzyme LxaN, which hydroxylates L-proline. 11- and 12-residue heinamides have the characteristic synergistic activity of laxaphycins against Aspergillus flavus FBCC 2467. Structural and genetic information of heinamides may prove useful in future discovery of natural products and drug development. ...
PublisherRoyal Society of Chemistry
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Additional information about fundingThis work was supported by a grant awarded to KS from the Jane and Aatos Erkko Foundation and LH was funded during the writing process by the Doctoral School of Environmental, Food and Biological Sciences of University of Helsinki.
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