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The γ-aminobutyric acid (GABA) shunt constitutes a conserved metabolic route generating nicotinamide adenine dinucleotide phosphate (NADPH) and regulating stress response in most organisms. Here we show that in the presence of GABA,  Saccharomyces cerevisiae  produces glutamate and alanine through the irreversible action of Uga1 transaminase. Alanine induces expression of alanine transaminase ( ALT1 ) gene. In an  alt1 Δ mutant grown on GABA, alanine accumulation leads to repression of the  GAD1 ,  UGA1 , and  UGA2  genes, involved in the GABA shunt, which could result in growth impairment. Induced  ALT1  expression and negative modulation of the GABA shunt by alanine constitute a novel regulatory circuit controlling both alanine biosynthesis and catabolism. Consistent with this, the GABA shunt and the production of NADPH are repressed in a wild-type strain grown in alanine, as compared to those detected in the wild-type strain grown on GABA. We also show that heat shock induces alanine biosynthesis and  ALT1 ,  UGA1 ,  UGA2 , and  GAD1  gene expression, whereas an  uga1 Δ mutant shows heat sensitivity and reduced NADPH pools, as compared with those observed in the wild-type strain. Additionally, an  alt1 Δ mutant shows an unexpected alanine-independent phenotype, displaying null expression of mitochondrial  COX2 ,  COX3 , and  ATP6  genes and a notable decrease in mitochondrial/nuclear DNA ratio, as compared to a wild-type strain, which results in a petite phenotype. Our results uncover a new negative role of alanine in stress defense, repressing the transcription of the GABA shunt genes, and support a novel Alt1 moonlighting function related to the maintenance of mitochondrial DNA integrity and mitochondrial gene expression.

Alanine Represses γ-Aminobutyric Acid Utilization and Induces Alanine Transaminase Required for Mitochondrial Function in Saccharomyces cerevisiae