Homoserine Toxicity in Saccharomyces cerevisiae and Candida albicans Homoserine Kinase (thr1Δ) Mutants

In addition to threonine auxotrophy, mutation of the Saccharomyces cerevisiae threonine biosynthetic genes THR1 (encoding homoserine kinase) and THR4 (encoding threonine synthase) results in a plethora of other phenotypes. We investigated the basis for these other phenotypes and found that they are dependent on the toxic biosynthetic intermediate homoserine. Moreover, homoserine is also toxic for Candida albicans thr1Δ mutants. Since increasing levels of threonine, but not other amino acids, overcome the homoserine toxicity of thr1Δ mutants, homoserine may act as a toxic threonine analog. Homoserine-mediated lethality of thr1Δ mutants is blocked by cycloheximide, consistent with a role for protein synthesis in this lethality. We identified various proteasome and ubiquitin pathway components that either when mutated or present in high copy numbers suppressed the thr1Δ mutant homoserine toxicity. Since the doa4Δ and proteasome mutants identified have reduced ubiquitin- and/or proteasome-mediated proteolysis, the degradation of a particular protein or subset of proteins likely contributes to homoserine toxicity.