title: The polyketide synthase Pks13 catalyzes a novel mechanism of lipid transfer in mycobacteria.
abstract: Mycolate-containing compounds constitute major strategic elements of the protective coat surrounding the tubercle bacillus. We have previously shown that FAAL32-Pks13 polyketide synthase catalyzes the condensation reaction, which produces α-alkyl β-ketoacids, direct precursors of mycolic acids. In contrast to the current biosynthesis model, we show here that Pks13 catalyzes itself the release of the neosynthesized products and demonstrate that this function is carried by its thioesterase-like domain. Most importantly, in agreement with the prediction of a trehalose-binding pocket in its catalytic site, this domain exhibits an acyltransferase activity and transfers Pks13's products onto an acceptor molecule, mainly trehalose, leading to the formation of the trehalose monomycolate precursor. Thus, this work allows elucidation of the hinge step of the mycolate-containing compound biosynthesis pathway. Above all, it highlights a unique mechanism of transfer of polyketide synthase products in mycobacteria, which is distinct from the conventional intervention of the discrete polyketide-associated protein (Pap)-type acyltransferases.
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Sabine
authors.initials: S
authors.lastname: Gavalda
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Bardou
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Laval
authors.affiliation: Department Biologie Structurale et Biophysique, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Bon
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Wladimir
authors.initials: W
authors.lastname: Malaga
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chalut
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilhot
authors.affiliation: Department Biologie Structurale et Biophysique, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Lionel
authors.initials: L
authors.lastname: Mourey
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France.
authors.forename: Mamadou
authors.initials: M
authors.lastname: Daffé
authors.affiliation: Department Tuberculose & Biologie des Infections, CNRS, IPBS (Institut de Pharmacologie et de Biologie Structurale), UMR5089, 205 route de Narbonne, BP64182, 31077 Toulouse, France; Université de Toulouse, UPS, IPBS, 31077 Toulouse, France. Electronic address: annaik.quemard@ipbs.fr.
authors.forename: Annaïk
authors.initials: A
authors.lastname: Quémard
mesh_terms: D000217:Acyltransferases / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism*; D055162:Biocatalysis; D008958:Models, Molecular; D009171:Mycolic Acids / Q000378:metabolism*; D048630:Polyketide Synthases / Q000737:chemistry / Q000378:metabolism*; D011108:Polymers / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013379:Substrate Specificity; D014199:Trehalose / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D009171:Mycolic Acids; D011108:Polymers; C576758:polyketide synthase Pks13, Mycobacterium tuberculosis; C024617:polyol; D048630:Polyketide Synthases; D014199:Trehalose; D000217:Acyltransferases