Journal
ACS CHEMICAL BIOLOGY
Volume 17, Issue 9, Pages 2528-2537Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.2c00464
Keywords
-
Categories
Funding
- European Research Council [759840]
- European Union's Horizon 2020 programme (WIDESPREAD) [SFRH/BD/138308/2018]
- Fundacao para a Cie<^>ncia e a Tecnologia (FCT) [CHE-1454007]
- FCT [CHE-2003436]
- Fulbright Commission
- Harvard University
- National Science Foundation (NSF) [1907240]
- NSF Postdoctoral Research Fellowship in Biology
- [952374]
- [UIDB/04423/2020]
- Fundação para a Ciência e a Tecnologia [UIDB/04423/2020, SFRH/BD/138308/2018] Funding Source: FCT
- European Research Council (ERC) [759840] Funding Source: European Research Council (ERC)
- Div Of Biological Infrastructure
- Direct For Biological Sciences [1907240] Funding Source: National Science Foundation
Ask authors/readers for more resources
The biosynthesis of nocuolin A, a cytotoxic cyanobacterial metabolite, was investigated. It was found that the carbon skeleton of nocuolin A is assembled from two medium-chain fatty acids, hexanoic and octanoic acids, and the 3-hydroxypropanoyl moiety originates from methionine. The study provides insight into the unusual biosynthetic chemistry of nocuolin A.
Nocuolin A is a cytotoxic cyanobacterial metabolite that is proposed to be produced by enzymes of the noc biosynthetic gene cluster. Nocuolin A features a 1,2,3-oxadiazine moiety, a structural feature unique among natural products and, so far, inaccessible through organic synthesis, suggesting that novel enzymatic chemistry might be involved in its biosynthesis. This heterocycle is substituted with two alkyl chains and a 3-hydroxypropanoyl moiety. We report here our efforts to elucidate the origin of the carbon skeleton of nocuolin A. Supplementation of cyanobacterial cultures with stable isotope-labeled fatty acids revealed that the central C-13 chain is assembled from two medium-chain fatty acids, hexanoic and octanoic acids. Using biochemical assays, we show that a fatty acyl-AMP ligase, NocH, activates both fatty acids as acyl adenylates, which are loaded onto an acyl carrier protein domain and undergo a nondecarboxylative Claisen condensation catalyzed by the ketosynthase NocG. This enzyme is part of a phylogenetically well-defined clade within similar genomic contexts. NocG presents a unique combination of characteristics found in other ketosynthases, namely in terms of substrate specificity and reactivity. Further supplementation experiments indicate that the 3-hydroxypropanoyl moiety of 1 originates from methionine, through an as-yet-uncharacterized mechanism. This work provides ample biochemical evidence connecting the putative noc biosynthetic gene cluster to nocuolin A and identifies the origin of all its carbon atoms, setting the stage for elucidation of its unusual biosynthetic chemistry.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available