title: Dissecting the functional role of polyketide synthases in Dictyostelium discoideum: biosynthesis of the differentiation regulating factor 4-methyl-5-pentylbenzene-1,3-diol.
abstract: 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.
authors.affiliation: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, India.
authors.forename: Ratna
authors.initials: R
authors.lastname: Ghosh
authors.forename: Arush
authors.initials: A
authors.lastname: Chhabra
authors.forename: Pallavi A
authors.initials: PA
authors.lastname: Phatale
authors.forename: Subodh K
authors.initials: SK
authors.lastname: Samrat
authors.forename: Jyoti
authors.initials: J
authors.lastname: Sharma
authors.forename: Anuradha
authors.initials: A
authors.lastname: Gosain
authors.forename: Debasisa
authors.initials: D
authors.lastname: Mohanty
authors.forename: Shweta
authors.initials: S
authors.lastname: Saran
authors.forename: Rajesh S
authors.initials: RS
authors.lastname: Gokhale
mesh_terms: D000818:Animals; D002474:Cell-Free System; D019295:Computational Biology; D004023:Dictyostelium / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D007700:Kinetics; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D008956:Models, Chemical; D010802:Phylogeny; D048630:Polyketide Synthases / Q000378:metabolism*; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012118:Resorcinols / Q000378:metabolism*; D012984:Software
chemical_list: C511448:4-methyl-5-pentylbenzene-1,3-diol; D012118:Resorcinols; D048630:Polyketide Synthases; D008780:Methyltransferases