Mycobacterium tuberculosis is the aetiological agent of tuberculosis, which is the single leading cause of human mortality by an infectious disease. beta-ketoacyl acyl carrier protein synthases (KAS) are essential enzymes of fatty acid biosynthesis (FAS) and catalyze condensation reactions resulting in elongation of fatty acyl chains. The fatty acyl products of the FAS system are critical precursors of mycobacterial cell wall components. Owing to the essentiality of the cell wall to the survival of the pathogen inside its human host the KAS enzymes have been identified as targets for development of novel drugs to combat this pathogen. Studies of three dimensional structures of these enzymes are important for the design of inhibitors and ultimately new drugs against M. tuberculosis. This dissertation describes the X-ray crystal structure studies of two of the KAS enzymes, beta-ketoacyl acyl carrier protein synthases II and III from M. tuberculosis. Unique features identified in these structures give clues to understand acyl substrate binding in these enzymes. A new scheme is proposed for the transacylation half reaction of beta-ketoacyl acyl carrier protein synthase III enzyme activity. The structure of beta-ketoacyl acyl carrier protein synthase II has been used to model its interaction with a known inhibitor, thiolactomycin (TLM). The model suggests modifications that could be done to the TLM scaffold to obtain analogs with better stereochemical fit. This dissertation also describes structure determination of a small protein, HPr from Bacillus stearothermophilus . Analysis of a novel structure of this protein is described and the implication discussed.LIST OF FIGURES FIGURE Page 1 Schematic diagram of mycobacterial cell wall 33 2 Schematic diagram of the ... of m^FabH 93 8 Structure based alignment of various FabH sequences 96 9 Ribbon representation of m^FabH dimer 98 10anbsp;...
|Title||:||X-ray Crystal Structure Studies of Mycobacterium Tuberculosis Beta-ketoacyl Acyl Carrier Protein Synthases and Bacillus Stearothermophilus HPr Protein|
|Publisher||:||ProQuest - 2006|