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A ROLE FOR PROTEIN KINASE G IN FOLATE METABOLISM AND INTRACELLULAR SURVIVAL IN MYCOBACTERIA

Wolff, Kerstin Andrea

Abstract Details

2012, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.

The eukaryotic-like serine/threonine protein kinase G (PknG) of Mycobacterium tuberculosis has been shown to be important for survival of the bacillus in host macrophages, presumably by preventing lysosomal delivery. It was therefore suggested that PknG serves as a virulence factor, although the underlying mechanism has remained uncharacterized.

Here we present evidence that PknG regulates de novo folate biosynthesis that is required for static growth conditions including those found in surface biofilms and in host macrophages. Deletion of pknG resulted in defects in folate synthesis, growth under static conditions, as well as resistance of mycobacterial species to classical antifolates and other antibiotics. We have identified a novel substrate for PknG, the ribosomal protein RplM of the large ribosomal subunit. RplM is phosphorylated by PknG at a unique, mycobacterially conserved residue, threonine 11, and co-purified with MutT3, a putative Nudix enzyme that exhibits a dihydroneopterin-triphosphate pyrophosphatase activity, catalyzing the first committed step of de novo folate biosynthesis. We demonstrate that inhibition of PknG has the potential to be exploited for potentiating the anti-mycobacterial activity of classical antifolate drugs and we present evidence that the previously demonstrated role of PknG in blocking phagolysosomal synthesis in infected host macrophages is mediated through its function in mycobacterial folate metabolism. Our work suggests that folate antagonism could be used to sensitize pathogenic mycobacteria to available chemotherapeutic reagents, as well as the innate bactericidal activity of host phagocytic cells.

Liem Nguyen, PhD (Advisor)
Arne Rietsch, PhD (Committee Chair)
W.Henry Boom, MD (Committee Member)
Jonathan Karn, PhD (Committee Member)
231 p.

Recommended Citations

Citations

  • Wolff, K. A. (2012). A ROLE FOR PROTEIN KINASE G IN FOLATE METABOLISM AND INTRACELLULAR SURVIVAL IN MYCOBACTERIA [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1322846033

    APA Style (7th edition)

  • Wolff, Kerstin. A ROLE FOR PROTEIN KINASE G IN FOLATE METABOLISM AND INTRACELLULAR SURVIVAL IN MYCOBACTERIA. 2012. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1322846033.

    MLA Style (8th edition)

  • Wolff, Kerstin. "A ROLE FOR PROTEIN KINASE G IN FOLATE METABOLISM AND INTRACELLULAR SURVIVAL IN MYCOBACTERIA." Doctoral dissertation, Case Western Reserve University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=case1322846033

    Chicago Manual of Style (17th edition)