4b3j

Publication Abstract from PubMed

The incidence of tuberculosis is increasing due to the appearance of new drug resistant variants. A thorough understanding of the disease organism is essential in order to create more effective drugs. In an attempt to understand better the poorly studied lipid metabolism of Mycobacterium tuberculosis (Mtb) we identified and characterized its fatty acid beta-oxidation complex (trifunctional enzyme (TFE)). TFE is an alpha2beta2 complex consisting of two types of polypeptides catalyzing three of the four reactions of the beta-oxidation of fatty acids. The kinetic constants (kcat and Km) show that the complexed alpha-chain is more active than the individual alpha-chain. Crystal structures of Mtb TFE (mtTFE) reveal that the quaternary assembly is strikingly different from the already known Pseudomonas fragi TFE (pfTFE) assembly due to the presence of a helical insertion (LA5) in the mtTFE-beta subunit. This helical insertion prevents the pfTFE mode of assembly, as it would clash with helix H9A of the TFE-alpha chain. The mtTFE assembly appears to be more rigid and results in a different substrate channeling path between the alpha and the beta subunits. Structural comparisons suggest that the mtTFE active sites can accommodate bulkier fatty acyl chains than in pfTFE. Although another thiolase (FadA2), more closely related to human TFE-beta/thiolase is present in the Mtb genome, it does not form a complex with mtTFE-alpha. Extensive phylogenetic analyses show that there are at least four TFE-subfamilies. Our studies highlight the molecular properties of mtTFE, significantly extending the structural knowledge on this type of very interesting multifunctional enzymes.

Structure of mycobacterial beta-oxidation trifunctional enzyme reveals its altered assembly and putative substrate channeling pathway.,Venkatesan R, Wierenga RK ACS Chem Biol. 2013 Mar 15. PMID:23496842^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.