title: Structural Characterisation of the Beta-Ketoacyl-Acyl Carrier Protein Synthases, FabF and FabH, of Yersinia pestis.
abstract: Yersinia pestis, the causative agent of bubonic, pneumonic, and septicaemic plague, remains a major public health threat, with outbreaks of disease occurring in China, Madagascar, and Peru in the last five years. The existence of multidrug resistant Y. pestis and the potential of this bacterium as a bioterrorism agent illustrates the need for new antimicrobials. The β-ketoacyl-acyl carrier protein synthases, FabB, FabF, and FabH, catalyse the elongation of fatty acids as part of the type II fatty acid biosynthesis (FASII) system, to synthesise components of lipoproteins, phospholipids, and lipopolysaccharides essential for bacterial growth and survival. As such, these enzymes are promising targets for the development of novel therapeutic agents. We have determined the crystal structures of the Y. pestis β-ketoacyl-acyl carrier protein synthases FabF and FabH, and compared these with the unpublished, deposited structure of Y. pestis FabB. Comparison of FabB, FabF, and FabH provides insights into the substrate specificities of these enzymes, and investigation of possible interactions with known β-ketoacyl-acyl carrier protein synthase inhibitors suggests FabB, FabF and FabH may be targeted simultaneously to prevent synthesis of the fatty acids necessary for growth and survival.
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Nanson
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
authors.forename: Zainab
authors.initials: Z
authors.lastname: Himiari
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.|E.H. Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
authors.forename: Crystall M D
authors.initials: CM
authors.lastname: Swarbrick
authors.affiliation: School of Biomedical Sciences, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.|E.H. Graham Centre for Agricultural Innovation, Charles Sturt University, Wagga Wagga, NSW, 2678, Australia.
authors.forename: Jade K
authors.initials: JK
authors.lastname: Forwood
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D000595:Amino Acid Sequence; D000627:Aminophenols / Q000737:chemistry / Q000494:pharmacology; D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011083:Polycyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D015010:Yersinia pestis / Q000201:enzymology* / Q000235:genetics
chemical_list: D000627:Aminophenols; D000890:Anti-Infective Agents; D004791:Enzyme Inhibitors; D011083:Polycyclic Compounds; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase; C520340:platencin