Structural and biochemical characterization of a novel pathway for mycolic acid synthesis in Mycobacterium tuberculosis


Project leader


Funding source

Swedish Research Council - Vetenskapsrådet (VR)


Project Details

Start date: 01/02/2007
End date: 31/01/2011
Funding: 9864000 SEK


Description

Mycobacterium tuberculosis, the causative agent of tuberculosis, is one of the worst global killers with an estimated 2 billion people infected and 2 million yearly deaths. M. tuberculosis has an extremely complex lipid metabolism with several products that are unique to mycobacteria, for example mycolic acids (MAs). MAs make up a thick layer around the bacterium that protects it against immune responses as well as several antibiotics. One pathway for MA production has dominated the literature but recent cell biology experiments have identified a second plausible pathway. The seven enzymes in this pathway, encoded by the MymA operon, likely represent examples of challenging chemical reactions with substrates that are previously uncharacterized in detail. In this project I will study these enzymes structurally, biochemically and biophysically to define the pathway and exact functions of the enzymes. MA synthesis represents an extreme of lipid metabolism in nature; the products are chemically diverse, very large (60-90 carbon atoms) and make up some 50% of the dry weight of the cell envelope. Characterization of a second pathway for MA synthesis is thus scientifically interesting from both a biological and chemical perspective. Moreover, MA synthesis is a primary drug target. Inactivation of the MymA operon leads to increased sensitivity to antibiotics and reduced survival of the bacterium; the results from these studies can thus be directly applied in drug design efforts.


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Last updated on 2017-24-03 at 12:06