Heterologous expression in Saccharopolyspora erythraea of a pentaketide synthase derived from the spinosyn polyketide synthaseElectronic supplementary information (ESI) available: Further details of the construction of pCJR308, the fermentation of BIOT-0966 and the isolation of pentaketide lactone, 3, and figures showing the13C NMR and 1H COSY spectra of 3. See http://www.rsc.org/suppdata/ob/b3/b310740j/

Martin, Christine; Timoney, Máire C.; Sheridan, Rose; Kendrew, Steven G.; Wilkinson, Barrie; Staunton, James; Leadlay, Peter F.

doi:10.1039/b310740j

Cited by 39 publications

(10 citation statements)

References 12 publications

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“…[34,50,51] Thus, the primary determinant of its function would seem to be specificity for the substrate acyl group attached to the ACP and the presence of a suitably positioned nucleophile with which to accomplish lactonization or hydrolysis. [52,53] Similar conclusions supporting the role of proximity have recently been reached for recombinant PKS KR domains, which showed specificity for their b-ketoacylthioester substrates, but not for the ACP domains to which the substrates were tethered, nor for the KS domains that synthesized the intermediates.…”

Section: A C H T U N G T R E N N U N G Kinetic Data Suggest That Nonpmentioning

confidence: 98%

Covalent Linkage Mediates Communication between ACP and TE Domains in Modular Polyketide Synthases

et al. 2008

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Polyketide natural products such as erythromycin A and epothilone are assembled on multienzyme polyketide synthases (PKSs), which consist of modular sets of protein domains. Within these type I systems, the fidelity of biosynthesis depends on the programmed interaction among the multiple domains within each module, centered around the acyl carrier protein (ACP). A detailed understanding of interdomain communication will therefore be vital for attempts to reprogram these pathways by genetic engineering. We report here that the interaction between a representative ACP domain and its downstream thioesterase (TE) is mediated largely by covalent tethering through a short "linker" region, with only a minor energetic contribution from protein-protein molecular recognition. This finding helps explain in part the empirical observation that TE domains can function out of their normal context in engineered assembly lines, and supports the view that overall PKS architecture may dictate at least a subset of interdomain interactions.

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Section: A C H T U N G T R E N N U N G Kinetic Data Suggest That Nonpmentioning

confidence: 98%

Covalent Linkage Mediates Communication between ACP and TE Domains in Modular Polyketide Synthases

et al. 2008

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“…134,137 Intramolecular transesterification of the nascent ACP-bound polyketide results in elimination of the 22-member macrolactone 60 that is subsequently oxidized by the FAD-dependent SpnJ to form the ketone 61 . 138 A second post-PKS tailoring step catalyzed by SpnM results in the 1,4-dehydration of 61 to produce species 62 , which is susceptible to a transannular [4 + 2]-cycloaddition that results in the tricyclic product 63 with the same stereochemistry observed in the final product 59 .…”

Section: Spnfmentioning

confidence: 99%

Natural [4 + 2]-Cyclases

et al. 2016

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[4 + 2]-Cycloadditions are increasingly being recognized in the biosynthetic pathways of many structurally complex natural products. A relatively small collection of enzymes from these pathways have been demonstrated to increase rates of cyclization and impose stereochemical constraints on the reactions. While mechanistic investigation of these enzymes is just beginning, recent studies have provided new insights with implications for understanding their biosynthetic roles, mechanisms of catalysis and evolutionary origin.

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“…Much progress has been made in recent years in the development of expression strategies that are largely independent from the source and size of the genes [91][92][93][94][95]. Symbiotic producers of polyketides and nonribosomal peptides are likely to be only distantly related to cultivated bacteria and might therefore use promoters, codons and regulatory proteins that differ from those of established expression host.…”

Section: Future Perspectivesmentioning

confidence: 99%

Naturally Occurring and Synthetic Imidazoles: Their Chemistry and Their Biological Activities

Luca¹

2006

curr med chem

147

134

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Invertebrate animals, such as sponges, tunicates and bryozoans, are among the most important sources of biomedically relevant natural products. However, as these animals generally contain only low quantities of the compounds, further pharmacological development is in most cases difficult. There is increasing evidence that many metabolites, in particular polyketides and nonribosomally synthesized peptides, are not produced by the animals themselves but by associated bacterial symbionts. This symbiont hypothesis currently attracts considerable interest, since it implicates that animal-independent production systems based on bacterial fermentation processes could be created. This review gives an overview about recent developments in the research on natural product symbiosis. Different techniques will be discussed that have been employed to pinpoint the actual producer. Since bacterial symbionts are highly fastidious and have been generally resistant to cultivation attempts, emphasis will be laid on culture-independent strategies, such as cell separation approaches and the cloning of biosynthetic genes. These strategies have provided insights into possible sources of several natural products, e.g. the bryostatins, pederin, the onnamides, swinholide A and theopalauamide. Finally, potential techniques for the generation of renewable supplies of symbiont-derived drug candidates will be discussed. Cultivation approaches and the heterologous expression of cloned biosynthesis genes from uncultured symbionts could in future provide access to several important marine drug candidates, including bryostatin 1, halichondrin or ET-743.

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Cited by 39 publications

References 12 publications

Covalent Linkage Mediates Communication between ACP and TE Domains in Modular Polyketide Synthases

Covalent Linkage Mediates Communication between ACP and TE Domains in Modular Polyketide Synthases

Natural [4 + 2]-Cyclases

Naturally Occurring and Synthetic Imidazoles: Their Chemistry and Their Biological Activities

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