β-ketoacyl-acyl Carrier Protein (ACP) Synthase III-2 (FabH2) From Vibrio cholerae

The production of fatty acids are critical for the viability of all organisms, as they are used in a variety of vital biological processes including energy storage, biological membrane construction, and signal transduction. Thus bacterial fatty acid synthases (FAS) are attractive targets for the development of novel antibacterial agents. β-ketoacyl-acyl carrier protein (ACP) synthase III (FabH) is an especially promising target, since it catalyzes the first, rate-limiting condensation reaction to initiate the elongation cycle of fatty acid synthesis.

Most bacteria encode only one copy of FabH with substrate specificity towards acetyl-CoA. V. cholerae, the Gram-negative bacterium which causes cholera, possesses a second copy of FabH (FabH2) which exhibit different substrate specificity. Dr. Jing Hou of University of Virginia, in collaboration with researchers from the Center for Structural Genomics of Infectious Diseases (CSGID)​, has determined the first crystal structure of FabH2 and characterized the biological significance for the presence of FabH2 in V. cholerae (vcFabH2).

The crystal structure of vcFabH2 exhibits a unique, elongated C-terminus that forms extensive interactions with the substrate binding pocket and dimer interface, resulting in a much bigger dimer interface than most of FabH proteins with known structures and/or substrates. The distinctive substrate specificity of vcFabH2 towards medium-chain acyl-CoA was characterized by structural, kinetic and binding studies. Mutation of a cysteine residue in the elongated C-terminal fragment (C356) impairs the enzymatic activity of vcFabH2, reinforcing the indispensable role of this fragment. This research has laid a solid foundation for the understanding of vcFabH2 as a promising target for the development of new drugs, including antibacterials effective against multidrug resistant strains of V. cholerae.

 





Crystal structure of FabH2 from V. cholerae

Crystal structure of FabH2 from V. cholerae

Crystal structure of FabH2 from V. cholerae

All featured structures from the NIAID Structural Genomics Centers​​​

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