The Phormidolide Biosynthetic Gene Cluster: A <i>trans</i>‐AT PKS Pathway Encoding a Toxic Macrocyclic Polyketide

Bertin, Matthew J.; Vulpanovici, Alexandra; Monroe, Emily A.; Korobeynikov, Anton; Sherman, David H.; Gerwick, Lena; Gerwick, William H.

doi:10.1002/cbic.201500467

Cited by 38 publications

(60 citation statements)

References 61 publications

(162 reference statements)

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“…Our investigation of the secondary metabolite potential of a Leptolyngbya sp. collected from Sulawesi, Indonesia, led to the identification of a PKS pathway that was ultimately determined to encode for the toxic macrocyclic polyketide, phormidolide [2, 58]. This pathway possessed several unusual features from canonical PKS biosynthetic pathways and was annotated as a trans -AT system [2].…”

Section: Genome Mining: Identifying Trans-at Systems With Intriguing mentioning

confidence: 99%

“…Intriguingly, our examination of genomic data from several filamentous marine cyanobacteria has led to the identification of the first trans -AT pathway described from this sub-group of cyanobacteria, and raises interesting questions about the distribution of these pathways as well as trends in the construction of stereochemically complex macrocyclic polyketides in these taxa. The pathway contains several of the deviations from canonical PKS systems described above, including discrete ATs, split modules, non-elongating KS 0 domains, tandem ACP domains at β -branch points, and an HCS cassette [2] (Fig. 4).…”

Section: Genome Mining: Identifying Trans-at Systems With Intriguing mentioning

confidence: 99%

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Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

Moss

Bertin

Kleigrewe

et al. 2016

Journal of Industrial Microbiology and Biotechnology

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Filamentous marine cyanobacteria produce bioactive natural products with both potential therapeutic value and capacity to be harmful to human health. Genome sequencing has revealed that cyanobacteria have the capacity to produce many more secondary metabolites than have been characterized. The biosynthetic pathways that encode cyanobacterial natural products are mostly uncharacterized, and lack of cyanobacterial genetic tools has largely prevented their heterologous expression. Hence, a combination of cutting edge and traditional techniques has been required to elucidate their secondary metabolite biosynthetic pathways. Here, we review the discovery and refined biochemical understanding of the olefin synthase and fatty acid ACP reductase/aldehyde deformylating oxygenase pathways to hydrocarbons, and the curacin A, jamaicamide A, lyngbyabellin, columbamide, and a trans-acyltransferase macrolactone pathway encoding phormidolide. We integrate into this discussion the use of genomics, mass spectrometric networking, biochemical characterization, and isolation and structure elucidation techniques.

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Section: Genome Mining: Identifying Trans-at Systems With Intriguing mentioning

confidence: 99%

Section: Genome Mining: Identifying Trans-at Systems With Intriguing mentioning

confidence: 99%

Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

Moss

Bertin

Kleigrewe

et al. 2016

Journal of Industrial Microbiology and Biotechnology

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“…An initial MIBiG analysis of the clusters suggested for pks1 and pks4 congeners of cytotoxic phormidolides [11] and tartrolon-type antibiotics, [12] respectively,while those of pks2, pks3, pks5,a nd pks6 lacked architecturally similar clusters in any other sequenced bacterium in the GenBank database (Table S2). Intriguingly,w ith as ize of about 129 kb and 25 encoded PKS modules, pks3w as one of the largest known trans-ATPKS gene clusters at the time of writing,suggesting as tructurally distinct polyketide ( Figure 2a nd Table S3).…”

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Genome‐Based Identification of a Plant‐Associated Marine Bacterium as a Rich Natural Product Source

et al. 2018

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The large number of sequenced bacterial genomes provides the opportunity to bioinformatically identify rich natural product sources among previously neglected microbial groups. Testing this discovery strategy, unusually high biosynthetic potential was suggested for the Oceanospirillales member Gynuella sunshinyii, a Gram-negative marine bacterium from the rhizosphere of the halophilic plant Carex scabrifolia. Its genome contains numerous unusual biosynthetic gene clusters for diverse types of metabolites. Genome-guided isolation yielded representatives of four different natural product classes, of which only alteramide A was known. Cytotoxic lacunalides were identified as products of a giant trans-acyltransferase polyketide synthase gene cluster, one of six present in this strain. Cytological profiling against HeLa cells suggested that lacunalide A disrupts CDK signaling in the cell cycle. In addition, chemical studies on model compounds were conducted, suggesting the structurally unusual ergoynes as products of a conjugated diyne-thiourea cyclization reaction.

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“…Within their biosynthetic pathways, each of these catalyzes the formation of six-membered dihydropyran or tetrahyropyran (oxane) rings through the conjugate addition of a ζ-hydroxyl group to C β , except for the oocydin and phormidolide PSs, which produce five-membered tetrahydrofuran (oxolane) rings through an ε-hydroxyl group installed by a trans -acting monooxygenase. 10,11 Another unusual nucleophile for the PS reaction is the threonine side chain installed by a nonribosomal peptide synthetase (NRPS) module within the spliceostatin and thailanstatin NRPS/PKS hybrid pathways. 12,13 Possibly equivalent to the bifunctional AmbDH4, a DH in the fifth module of the misakinolide trans -AT assembly line (MisDH5) may perform both dehydration and pyran formation.…”

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Structural and Functional Studies of a Pyran Synthase Domain from a trans-Acyltransferase Assembly Line

et al. 2018

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trans-Acyltransferase assembly lines possess enzymatic domains often not observed in their better characterized cisacyltransferase counterparts. Within this repertoire of largely unexplored biosynthetic machinery is a class of enzymes called the pyran synthases that catalyze the formation of five- and sixmembered cyclic ethers from diverse polyketide chains. The 1.55 Å resolution crystal structure of a pyran synthase domain excised from the ninth module of the sorangicin assembly line highlights the similarity of this enzyme to the ubiquitous dehydratase domain and provides insight into the mechanism of ring formation. Functional assays of point mutants reveal the central importance of the active site histidine that is shared with the dehydratases as well as the supporting role of a neighboring semiconserved asparagine.

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The Phormidolide Biosynthetic Gene Cluster: A trans‐AT PKS Pathway Encoding a Toxic Macrocyclic Polyketide

Cited by 38 publications

References 61 publications

Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

Integrating mass spectrometry and genomics for cyanobacterial metabolite discovery

Genome‐Based Identification of a Plant‐Associated Marine Bacterium as a Rich Natural Product Source

Structural and Functional Studies of a Pyran Synthase Domain from a trans-Acyltransferase Assembly Line

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