A1 Journal article (refereed)
The structure and biosynthesis of heinamides A1–A3 and B1–B5, antifungal members of the laxaphycin lipopeptide family (2021)

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

JYU authors or editors

Publication details

All authors or editors: Heinilä, Lassi Matti Petteri; Fewer, David Peter; Jokela, Jouni Kalevi; Wahlsten, Matti; Ouyang, Xiaodan; Permi, Perttu; Jortikka, Anna; Sivonen, Kaarina

Journal or series: Organic and Biomolecular Chemistry

ISSN: 1477-0520

eISSN: 1477-0539

Publication year: 2021

Volume: 19

Issue number: 25

Pages range: 5577-5588

Publisher: Royal Society of Chemistry

Publication country: United Kingdom

Publication language: English

DOI: https://doi.org/10.1039/D1OB00772F

Publication open access: Openly available

Publication channel open access: Partially open access channel

Publication is parallel published (JYX): https://jyx.jyu.fi/handle/123456789/76345

Abstract

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.

Keywords: biosynthesis; peptides; amino acids; antimicrobial compounds

Contributing organizations

Ministry reporting: Yes

VIRTA submission year: 2021

JUFO rating: 1