Student Theses and Dissertations

Date of Award

2006

Document Type

Thesis

RU Laboratory

Rice Laboratory

Keywords

tuberculosis, glyoxylate metabolism, mycobacterium smegmatis

Abstract

Much has been learned about Mycobacterium tuberculosis, the causative agent of tuberculosis, “the great white plague,” since the bacterium was isolated and initially characterized by Robert Koch over a century ago. Over the last decade, new genetic tools for manipulation of the bacterium have been developed, its genome has been sequenced, and the search for new vaccines and drug targets has greatly intensified. Yet, surprisingly little is known about which mycobacterial genes are truly important for the organism’s ability to persist in the tissues of its human hosts. The metabolic pathways used by the tubercle bacillus to establish and maintain a life-long infection have largely been ignored by researchers, yet they may represent promising new areas for therapeutic intervention. Recently, one enzyme of the glyoxylate shunt of M. tuberculosis, isocitrate lyase (ICL), was shown to be required for virulence in experimental infections of mice. The other enzyme of the glyoxylate shunt, malate synthase (MLS), may also be important for the intracellular survival of the tubercle bacillus; yet, no studies have been done to determine its in vivo role. We present here results of genetic studies of MLS in the saprophyte Mycobacterium smegmatis, and show that MLS, unlike ICL, is dispensable for growth on acetate or fatty acids. We also describe the dglycerate pathway in M. smegmatis, which enables malate synthase-deficient bacteria to utilize acetate and fatty acids as sole carbon sources, and which allows M. smegmatis to grow on glyoxylate. The d-glycerate pathway, however, does not appear to exist in the pathogenic Mycobacterium tuberculosis.

Comments

A thesis presented to the faculty of The Rockefeller University in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Permanent URL

http://hdl.handle.net/10209/134

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