The structure and biosynthesis of heinamides A1-A3 and B1-B5, antifungal members of the laxaphycin lipopeptide family
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 antifung...
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Published in | Organic & biomolecular chemistry Vol. 19; no. 25; pp. 5577 - 5588 |
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Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
CAMBRIDGE
Royal Soc Chemistry
30.06.2021
Royal Society of Chemistry |
Subjects | |
Online Access | Get full text |
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Summary: | 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 (2
S
,4
R
)-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.
Laxaphycins are a family of cyclic lipopeptides with synergistic antifungal and antiproliferative activities. |
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Bibliography: | 10.1039/d1ob00772f Electronic supplementary information (ESI) available. See DOI ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1477-0520 1477-0539 1477-0539 |
DOI: | 10.1039/d1ob00772f |