Substrate Profile Analysis and ACP‐Mediated Acyl Transfer in <i>Streptomyces coelicolor</i> Type III Polyketide Synthases

Grüschow, Sabine; Buchholz, Tonia J.; Seufert, Wolfgang; Dordick, Jonathan S.; Sherman, David H.

doi:10.1002/cbic.200700026

Cited by 38 publications

(47 citation statements)

References 35 publications

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“…The transfer of acyl chains directly from the ACP domain to Type III PKS is uncommon. Two other examples of utilization of ACP/ thioester substrates by Type III PKS were reported recently in Streptomyces coelicolor (38,39). In conclusion, our study presents a new perspective of understanding the functional role of PKSs in producing signaling molecules, which may be crucial in the orchestration of the developmental stages in the life cycle of Dictyostelium.…”

Section: Discussionsupporting

confidence: 57%

Dissecting the Functional Role of Polyketide Synthases in Dictyostelium discoideum

Ghosh

Chhabra

Phatale

et al. 2008

Journal of Biological Chemistry

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Dictyostelium discoideum exhibits the largest repository of polyketide synthase (PKS) proteins of all known genomes. However, the functional relevance of these proteins in the biology of this organism remains largely obscure. On the basis of computational, biochemical, and gene expression studies, we propose that the multifunctional Dictyostelium PKS (DiPKS) protein DiPKS1 could be involved in the biosynthesis of the differentiation regulating factor 4-methyl-5-pentylbenzene-1,3-diol (MPBD). Our cell-free reconstitution studies of a novel acyl carrier protein Type III PKS didomain from DiPKS1 revealed a crucial role of protein-protein interactions in determining the final biosynthetic product. Whereas the Type III PKS domain by itself primarily produces acyl pyrones, the presence of the interacting acyl carrier protein domain modulates the catalytic activity to produce the alkyl resorcinol scaffold of MPBD. Furthermore, we have characterized an O-methyltransferase (OMT12) from Dictyostelium with the capability to modify this resorcinol ring to synthesize a variant of MPBD. We propose that such a modification in vivo could in fact provide subtle variations in biological function and specificity. In addition, we have performed systematic computational analysis of 45 multidomain PKSs, which revealed several unique features in DiPKS proteins. Our studies provide a new perspective in understanding mechanisms by which metabolic diversity could be generated by combining existing functional scaffolds.

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Section: Discussionsupporting

confidence: 57%

Dissecting the Functional Role of Polyketide Synthases in Dictyostelium discoideum

Ghosh

Chhabra

Phatale

et al. 2008

Journal of Biological Chemistry

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“…The transfer of the fatty acids from the ACP domain of ArsA to ArsB and ArsC implies that these type III PKSs can accept the starter fatty acids not only from CoA but also from ACP. Very recently, SCO7671, a type III PKS in Streptomyces coelicolor A3(2), has been shown to accept acyl-ACP as a starter substrate in vitro (25), although its biological role is unknown. These intriguing findings warrant future structural and mechanistic studies.…”

Section: Discussionmentioning

confidence: 99%

Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis

Miyanaga

Funa

Awakawa

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Alkylresorcinols and alkylpyrones, which have a polar aromatic ring and a hydrophobic alkyl chain, are phenolic lipids found in plants, fungi, and bacteria. In the Gram-negative bacterium Azotobacter vinelandii, phenolic lipids in the membrane of dormant cysts are essential for encystment. The aromatic moieties of the phenolic lipids in A. vinelandii are synthesized by two type III polyketide synthases (PKSs), ArsB and ArsC, which are encoded by the ars operon. However, details of the synthesis of hydrophobic acyl chains, which might serve as starter substrates for the type III polyketide synthases (PKSs), were unknown. Here, we show that two type I fatty acid synthases (FASs), ArsA and ArsD, which are members of the ars operon, are responsible for the biosynthesis of C 22-C26 fatty acids from malonyl-CoA. In vivo and in vitro reconstitution of phenolic lipid synthesis systems with the Ars enzymes suggested that the C 22-C26 fatty acids produced by ArsA and ArsD remained attached to the ACP domain of ArsA and were transferred hand-to-hand to the active-site cysteine residues of ArsB and ArsC. The type III PKSs then used the fatty acids as starter substrates and carried out two or three extensions with malonylCoA to yield the phenolic lipids. The phenolic lipids in A. vinelandii were thus found to be synthesized solely from malonyl-CoA by the four members of the ars operon. This is the first demonstration that a type I FAS interacts directly with a type III PKS through substrate transfer.Azotobacter vinelandii ͉ alkylresorcinol ͉ alkylpyrone ͉ long-chain fatty acid ͉ cyst

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“…Both enzymes can utilize the same long-chain acyl-CoA as a starter and catalyze three successive decarboxylative A type III polyketide synthase in S. coelicolor (locus tag: SCO7671) efficiently utilizes benzoyl-CoA and the branched iso-butyryl-CoA as starters to form pyrones. In addition, SCO7671 and GCS condensed malonyl-CoA with hexanoyl-ACP to yield pyrones; this is the first time type III PKSs were found to utilize acyl-ACPs [74,75]. Both PKSs are capable of accommodating huge macromolecular substrates as acyl carriers, presenting a novel means to manipulate PKSs to expand their repertoire of biosynthesized products.…”

Section: Other Bacterial Type III Pkssmentioning

confidence: 96%

Exploiting the Biosynthetic Potential of Type III Polyketide Synthases

Lim

Yew

2016

Molecules

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Abstract:Polyketides are structurally and functionally diverse secondary metabolites that are biosynthesized by polyketide synthases (PKSs) using acyl-CoA precursors. Recent studies in the engineering and structural characterization of PKSs have facilitated the use of target enzymes as biocatalysts to produce novel functionally optimized polyketides. These compounds may serve as potential drug leads. This review summarizes the insights gained from research on type III PKSs, from the discovery of chalcone synthase in plants to novel PKSs in bacteria and fungi. To date, at least 15 families of type III PKSs have been characterized, highlighting the utility of PKSs in the development of natural product libraries for therapeutic development.

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Substrate Profile Analysis and ACP‐Mediated Acyl Transfer in Streptomyces coelicolor Type III Polyketide Synthases

Cited by 38 publications

References 35 publications

Dissecting the Functional Role of Polyketide Synthases in Dictyostelium discoideum

Dissecting the Functional Role of Polyketide Synthases in Dictyostelium discoideum

Direct transfer of starter substrates from type I fatty acid synthase to type III polyketide synthases in phenolic lipid synthesis

Exploiting the Biosynthetic Potential of Type III Polyketide Synthases

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