In Vitro Transcriptional Activation by a Metabolic Intermediate: Activation by Leu3 Depends on α-Isopropylmalate

In the absence of the leucine biosynthetic precursor α-isopropylmalate (α-IPM), the yeast LEU3 protein (Leu3p) binds DNA and acts as a transcriptional repressor in an in vitro extract. Addition of α-IPM resulted in a dramatic increase in Leu3p-dependent transcription. The presence of α-IPM was also required for Leu3p to compete effectively with another transcriptional activator, GAL4/VP16, for limiting transcription factors. Therefore, the addition of α-IPM appears to convert a transcriptional repressor into an activator. This represents an example in eukaryotes of direct transcriptional regulation by a small effector molecule.