Biosynthesis of Chlorinated Lactylates in <i>Sphaerospermopsis</i> sp. LEGE 00249

Abt, Kathleen; Castelo-Branco, Raquel; Leão, Pedro N.

doi:10.1021/acs.jnatprod.0c00950

Cited by 9 publications

(12 citation statements)

References 54 publications

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“…In the structurally related chlorosphaerolactylates from Sphaerospermopsis sp.L EGE 00249, the lactyl stereogenic center was determined experimentally to be of S configuration. [41] This matched the bioinformatics prediction for the KR domain in the ClyF depsipeptide synthetase, [42] responsible for the generation of the stereogenic center.I n Nodularia sp.L EGE 06071, ClyF-KR (83 %i dentity,9 4% similarity to ClyF-KR from Sphaerospermopsis sp.L EGE 00249) is also predicted to generate an S-configured product (Figure S36). With this,t he absolute configuration of compounds 10-14 is proposed as 4R,1 8 S.…”

Section: Resultssupporting

confidence: 68%

“…Ap ortion of the % 40 kb BGC putatively assigned to 1 (noc), on the basis of comparative genomics, [40] was recently proposed to produce the chlorosphaerolactylates and renamed as cly. [42] We sequenced and searched the genome of Nodularia sp.LEGE 06071 for a noc/ cly locus,w hich we found within a2 26 kb contig.T he Sphaerospermopsis sp.L EGE 00249 cly BGC encodes two halogenases,w hich is consistent with the two halogenated positions in the alkyl chain of the chlorosphaerolactylates (Figure 5b). [42] Likewise,t he Nodularia sp.L EGE 06071 cly cluster encodes one halogenase,a nd as ingle halogenated carbon is present in 10 and 11 (Figure 5b).…”

Section: Resultsmentioning

confidence: 99%

“…[42] We sequenced and searched the genome of Nodularia sp.LEGE 06071 for a noc/ cly locus,w hich we found within a2 26 kb contig.T he Sphaerospermopsis sp.L EGE 00249 cly BGC encodes two halogenases,w hich is consistent with the two halogenated positions in the alkyl chain of the chlorosphaerolactylates (Figure 5b). [42] Likewise,t he Nodularia sp.L EGE 06071 cly cluster encodes one halogenase,a nd as ingle halogenated carbon is present in 10 and 11 (Figure 5b). The noc/cly locus exhibits an overall similar architecture in these and other strains that produce 1 [40] (Figure 5b).…”

Section: Resultsmentioning

confidence: 99%

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Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues**

et al. 2021

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In recent years,extensive sequencing and annotation of bacterial genomes has revealed an unexpectedly large number of secondary metabolite biosynthetic gene clusters whose products are yet to be discovered. Fore xample, cyanobacterial genomes contain avariety of gene clusters that likely incorporate fatty acid derived moieties,b ut for most cases we lack the knowledge and tools to effectively predict or detect the encoded natural products.H ere,w ee xploit the apparent absence of af unctional b-oxidation pathway in cyanobacteria to achieve efficient stable-isotope-labeling of their fatty acid derived lipidome.W es how that supplementation of cyanobacterial cultures with deuterated fatty acids can be used to easily detect natural product signatures in individual strains.T he utility of this strategy is demonstrated in two cultured cyanobacteria by uncovering analogues of the multidrug-resistance reverting hapalosin, and novel, cytotoxic, lactylate-nocuolin Ah ybrids-the nocuolactylates.

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Section: Resultssupporting

confidence: 68%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues**

et al. 2021

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“…As mentioned before, in cyanobacteria, deuterated fatty acids do not lose their label to being catabolized, but are elongated and incorporated into various metabolites. 21,36 We used a sequence of perdeuterated evenchain fatty acids from octanoic to octadecanoic acid to supplement Fischerella sp. PCC 9431 cultures.…”

Section: Fischerazole Biosynthesis Involves Carbon Rearrangement Of H...mentioning

confidence: 99%

Fischerazoles A-C, cyanobacterial polychlorinated lipids featuring fatty acyl chain rearrangement

Figueiredo

Abt

Martins

et al. 2022

Preprint

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Fatty acyl moieties are a very common feature of cyanobacterial secondary metabolites. Using a recently developed method to discover fatty acyl-containing natural products, we detected and isolated three new lipopeptides – fisch-erazoles A-C (1-3) – from the cyanobacterium Fischerella sp. PCC 9431. These metabolites present extensive halo-genation in their fatty acyl moiety as well as an unusual pendant allyl alcohol. We analyzed the genome sequence of the producing cyanobacterium and identified a putative biosynthetic gene cluster associated with the fischera-zoles, based on bioinformatic analysis. Using stable-isotope precursor feeding experiments, we identified the key substrates for the biosynthesis of 1-3. Surprisingly, we found that hexadecanoic acid was fully incorporated into fischerazoles, despite the fact that these compounds have a linear 15-carbon chain. Additional feeding experiments with stable-isotope labeled fatty acids established a one-carbon contraction of the palmitic acid-derived alkyl chain, and that the remaining carbon branches out as part of the pendant allyl alcohol group. This rearrangement, which leads to the functionalization of a mid-chain aliphatic carbon, might be of interest for biocatalysis. Our findings reinforce the utility of metabolomics-based methods to uncover natural product scaffolds with a high degree of novelty.

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“…This proposal was based on the presence of genes encoding fatty acyl-AMP ligases (FAALs) and different nitrogen processing/incorporating enzymes in this locus ( Figure 1 b). 4 , 12 However, several of the putative noc genes have recently been implicated in the biosynthesis of chlorosphaerolactylates (e.g., 2 , Figure 1 b). 12 To acknowledge these findings, those genes were renamed as clyA - F , constituting the cly BGC.…”

Section: Introductionmentioning

confidence: 99%

Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A

et al. 2022

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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.

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Biosynthesis of Chlorinated Lactylates in Sphaerospermopsis sp. LEGE 00249

Cited by 9 publications

References 54 publications

Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues**

Discovery of Cyanobacterial Natural Products Containing Fatty Acid Residues**

Fischerazoles A-C, cyanobacterial polychlorinated lipids featuring fatty acyl chain rearrangement

Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A

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