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Fungal homoserine kinase (thr1Delta) mutants are attenuated in virulence and die rapidly upon threonine starvation and serum incubation.

Abstract
The fungally conserved subset of amino acid biosynthetic enzymes not present in humans offer exciting potential as an unexploited class of antifungal drug targets. Since threonine biosynthesis is essential in Cryptococcus neoformans, we further explored the potential of threonine biosynthetic enzymes as antifungal drug targets by determining the survival in mice of Saccharomyces cerevisiae homoserine kinase (thr1Delta) and threonine synthase (thr4Delta) mutants. In striking contrast to aspartate kinase (hom3Delta) mutants, S. cerevisiae thr1Delta and thr4Delta mutants were severely depleted after only 4 h in vivo. Similarly, Candida albicans thr1Delta mutants, but not hom3Delta mutants, were significantly attenuated in virulence. Consistent with the in vivo phenotypes, S. cerevisiae thr1Delta and thr4Delta mutants as well as C. albicans thr1Delta mutants were extremely serum sensitive. In both species, serum sensitivity was suppressed by the addition of threonine, a feedback inhibitor of Hom3p. Because mutation of the HOM3 and HOM6 genes, required for the production of the toxic pathway intermediate homoserine, also suppressed serum sensitivity, we hypothesize that serum sensitivity is a consequence of homoserine accumulation. Serum survival is critical for dissemination, an important virulence determinant: thus, together with the essential nature of C. neoformans threonine synthesis, the cross-species serum sensitivity of thr1Delta mutants makes the fungus-specific Thr1p, and likely Thr4p, ideal antifungal drug targets.
AuthorsJoanne M Kingsbury, John H McCusker
JournalEukaryotic cell (Eukaryot Cell) Vol. 9 Issue 5 Pg. 729-37 (May 2010) ISSN: 1535-9786 [Electronic] United States
PMID20305003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Chelating Agents
  • Threonine
  • Flucytosine
  • Phosphotransferases (Alcohol Group Acceptor)
  • homoserine kinase
  • Calcium
Topics
  • Animals
  • Calcium (metabolism)
  • Candida albicans (cytology, drug effects, enzymology, pathogenicity)
  • Chelating Agents (pharmacology)
  • Flucytosine (metabolism)
  • Hydrogen-Ion Concentration (drug effects)
  • Mice
  • Microbial Viability (drug effects)
  • Mutation (genetics)
  • Phenotype
  • Phosphotransferases (Alcohol Group Acceptor) (genetics)
  • Saccharomyces cerevisiae (cytology, drug effects, enzymology, pathogenicity)
  • Serum (metabolism)
  • Threonine (deficiency, pharmacology)
  • Virulence (drug effects)

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