title: Mycocerosic acid synthase exemplifies the architecture of reducing polyketide synthases.
abstract: Polyketide synthases (PKSs) are biosynthetic factories that produce natural products with important biological and pharmacological activities. Their exceptional product diversity is encoded in a modular architecture. Modular PKSs (modPKSs) catalyse reactions colinear to the order of modules in an assembly line, whereas iterative PKSs (iPKSs) use a single module iteratively as exemplified by fungal iPKSs (fiPKSs). However, in some cases non-colinear iterative action is also observed for modPKSs modules and is controlled by the assembly line environment. PKSs feature a structural and functional separation into a condensing and a modifying region as observed for fatty acid synthases. Despite the outstanding relevance of PKSs, the detailed organization of PKSs with complete fully reducing modifying regions remains elusive. Here we report a hybrid crystal structure of Mycobacterium smegmatis mycocerosic acid synthase based on structures of its condensing and modifying regions. Mycocerosic acid synthase is a fully reducing iPKS, closely related to modPKSs, and the prototype of mycobacterial mycocerosic acid synthase-like PKSs. It is involved in the biosynthesis of C20-C28 branched-chain fatty acids, which are important virulence factors of mycobacteria. Our structural data reveal a dimeric linker-based organization of the modifying region and visualize dynamics and conformational coupling in PKSs. On the basis of comparative small-angle X-ray scattering, the observed modifying region architecture may be common also in modPKSs. The linker-based organization provides a rationale for the characteristic variability of PKS modules as a main contributor to product diversity. The comprehensive architectural model enables functional dissection and re-engineering of PKSs.
authors.affiliation: Department Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Dominik A
authors.initials: DA
authors.lastname: Herbst
authors.affiliation: Department Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Roman P
authors.initials: RP
authors.lastname: Jakob
authors.affiliation: Department Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Franziska
authors.initials: F
authors.lastname: Zähringer
authors.affiliation: Department Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.
authors.forename: Timm
authors.initials: T
authors.lastname: Maier
mesh_terms: D000217:Acyltransferases / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D064429:Fatty Acid Synthases / Q000378:metabolism; D008958:Models, Molecular; D020102:Mycobacterium smegmatis / Q000201:enzymology; D010084:Oxidation-Reduction; D048630:Polyketide Synthases / Q000737:chemistry* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D037521:Virulence Factors
chemical_list: D037521:Virulence Factors; D048630:Polyketide Synthases; D000217:Acyltransferases; C044110:mycocerosic acid synthase; D064429:Fatty Acid Synthases