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Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A.

ABSTRACT: 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 C₁₃ 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.

SUBMITTER: Martins TP

PROVIDER: S-EPMC9486936 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A.

Martins Teresa P TP Glasser Nathaniel R NR Kountz Duncan J DJ Oliveira Paulo P Balskus Emily P EP Leão Pedro N PN

ACS chemical biology 20220831

Nocuolin A is a cytotoxic cyanobacterial metabolite that is proposed to be produced by enzymes of the <i>noc</i> 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 t ...[more]

PMID: 36044983

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Project description:Dyrosauridae is a clade of neosuchian crocodyliforms that diversified in terrestrial and aquatic environments across the Cretaceous-Paleogene transition. The postcranial anatomy of dyrosaurids has long been overlooked, obscuring both their disparity and their locomotive adaptations. Here we thoroughly describe of the postcranial remains of an unusually small dyrosaurid, Cerrejonisuchus improcerus, from the middle-late Paleocene Cerrejón Formation of Colombia, and we provide a wealth of new data concerning the postcranial anatomy of the key dyrosaurids: Congosaurus bequaerti and Hyposaurus rogersii. We identify a series of postcranial autapomorphies in Cerrejonisuchus improcerus (an elliptic-shaped odontoid laterally wide, a ulna possessing a double concavity, a fibula bearing a widely flattened proximal end, a pubis showing a large non-triangular distal surface) as well as functionally-important traits such as a relatively long ulna (85% of the humerus' length), short forelimb (83% of hindlimb's length), or thoracic vertebra bearing comparatively large lateral process (with widened parapophysis and diapophysis) along with strongly arched thoracic ribs allowing a more sturdy and cylindrical rib cage. These indicate a more terrestrial lifestyle for Cerrejonisuchus compared to the derived members of the clade. We also built a dataset of 187 traits on 27 taxa, that extensively samples the cranial and postcranial architectures of exemplar crocodyliforms. We analyze these data in via Principal Coordinate Analysis (PCoA) to visualize the postcranial morphospace occupation of Dyrosauridae, Thalattosuchia, and Crocodylia. Our data reveal the existence of a distinctive postcranial anatomy for Dyrosauridae that is markedly distinct from that of crocodylians. As a result, modern crocodylians are probably not good functional analog for extinct crocodyliformes. Postcranial data should also be more widely used in phylogenetic and disparity analyses of Crocodyliformes.

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Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A.

Publications

Biosynthesis of the Unusual Carbon Skeleton of Nocuolin A.

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