Abstract/Details

X-ray crystal structure studies of <i>Mycobacterium tuberculosis</i> β-ketoacyl acyl carrier protein synthases and <i>Bacillus stearothermophilus</i> HPr protein


2006 2006

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Abstract (summary)

Mycobacterium tuberculosis is the aetiological agent of tuberculosis, which is the single leading cause of human mortality by an infectious disease. β-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, β-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 β-ketoacyl acyl carrier protein synthase III enzyme activity. The structure of β-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.

Indexing (details)


Subject
Biochemistry;
Molecular biology;
Biomedical research
Classification
0487: Biochemistry
0307: Molecular biology
0541: Biomedical research
Identifier / keyword
Applied sciences; Pure sciences; Biological sciences; Bacillus stearothermophilus; HPr; Ketoacyl acyl carrier protein synthases-beta; Mycobacterium tuberculosis
Title
X-ray crystal structure studies of <i>Mycobacterium tuberculosis</i> β-ketoacyl acyl carrier protein synthases and <i>Bacillus stearothermophilus</i> HPr protein
Author
Sridharan, Sudharsan
Number of pages
194
Publication year
2006
Degree date
2006
School code
1388
Source
DAI-B 67/09, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542882005
Advisor
Sacchettini, James C.
University/institution
The Texas A&M University System Health Science Center
University location
United States -- Texas
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3234291
ProQuest document ID
304910698
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304910698
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