Identification of Uga3 as an iron‐regulated transcription factor controlling the activity of the GABA shunt in Saccharomyces cerevisiae

Abstract

Yeast cells respond to iron deprivation by activating iron uptake, by mobilizing stored iron, and by repressing some iron-dependent metabolic pathways. GLT1 encodes glutamate synthase, an Fe-S cluster enzyme that is transcriptionally activated in iron-replete cells. We have identified Uga3 as an iron-dependent transcriptional activator of GLT1 and GAD1, which encodes glutamate decarboxylase. Uga3 is required for the activation of genes involved in the use of (-amino butyric acid (GABA) as a nitrogen source. Under iron-replete conditions, Uga3 binds to and transcriptionally activates a set of genes that convert (-ketoglutarate to succinate via glutamate and GABA. Under iron-depleted conditions, Uga3 levels are reduced 5–10-fold, and Uga3 target genes are expressed at very low levels. Uga3 is itself activated by GABA, which is produced by Gad1p. Thus, iron activates a positive feedback cycle in which Glt1p and Gad1p produce GABA, which activates Uga3p, which then increases the expression of GLT1 and GAD1. Transcription of GLT1 and GAD1, but not UGA3, is also dependent on Yap5p, another iron-sensing transcription factor. Microarray analysis suggests a role for Uga3p and iron in controlling the flux of TCA cycle intermediates into biosynthetic pathways.