PgmNr Y3006: Mmf1p protects Hem1p from damage caused by the ubiquitous metabolic stressor, 2-aminoacrylate.

Authors:
Dustin C. Ernst; Diana M. Downs


Institutes
University of Georgia, Athens, GA.


Keyword: Cell Cycle/Growth Control/Metabolism

Abstract:

Members of the RidA/YER057c/UK114 protein family are observed throughout each kingdom of life. Despite being widespread, a biochemical role for these proteins in vivo remained elusive until work in Salmonella enterica showed RidA prevents free 2-aminoacrylate (2AA) accumulation. Strains lacking RidA experienced 2AA stress, revealed as damage to a variety of metabolic enzymes and decreased fitness. The generation of 2AA in S. enterica was dependent on the activity of pyridoxal 5’-phosphate (PLP)-dependent serine/threonine dehydratases (IlvA/TdcB; EC 4.3.1.19). Previous studies of Saccharomyces cerevisiae RidA homologs, Mmf1p (mitochondrial) and Hmf1p (cytosolic), showed the lack of Mmf1p resulted in a petite growth phenotype. Given the paradigm described for S. enterica, we hypothesized that 2AA accumulation, and the resulting damage to a PLP-dependent enzyme, was responsible for the growth phenotypes observed for S. cerevisiae ∆mmf1 strains. The nuclear encoded serine/threonine dehydratases, Ilv1p (anabolic) and Cha1p (catabolic), are both localized to the mitochondrial matrix. When Ilv1p and Cha1p are simultaneously disrupted, respiratory activity is maintained in a ∆mmf1 background. These results showed that diminished respiratory activity in the absence of Mmf1p is a consequence of 2AA formation.  The paradigm in S. enterica suggested that the target for 2AA stress would be a PLP enzyme. Our data show that the first step in heme production, catalyzed by PLP-dependent aminolevulinic acid (ALA) synthase (Hem1p; EC 2.3.1.37), is inhibited in the absence of Mmf1p under conditions where 2AA is predicted to accumulate. Consistent with previous reports, diminished ALA production in S. cerevisiae adversely impacted respiration, perhaps highlighting a role for Mmf1p in maintaining Hem1 activity.



Yeast Database Genetic Index
1. gene symbol: mmf1; systematic name: YIL051C
2. gene symbol: hmf1; systematic name: YER057C
3. gene symbol: ilv1; systematic name: YER086W
4. gene symbol: cha1; systematic name: YCL064C
5. gene symbol: hem1; systematic name: YDR232W