In Saccharomyces cerevisae, feedback inhibition of homocitrate synthase isoenzymes by lysine modulates the activation of LYS gene expression by Lys14p

Expression of the structural genes for lysine biosynthesis responds to an i nduction mechanism mediated by the transcriptional activator Lys14p in the presence of alpha-aminoadipate semialdehyde (alpha AASA), an intermediate o f the pathway acting as a coinducer. This activation is reduced by the pres ence of lysine in the growth medium, leading to apparent repression. In this report we demonstrate that Saccharomyces cerevisiae possesses two g enes, LYS20 and LYS21, encoding two homocitrate synthase isoenzymes which a re located in the nucleus. Each isoform is inhibited by lysine with a diffe rent sensitivity. Lysine-overproducing mutants were isolated as resistant t o aminoethylcysteine, a toxic lysine analog. Mutations, LYS20(fbr) and LYS2 1(fbr), are allelic to LYS20 and LYS21, and lead to desensitization of homo citrate synthase activity towards lysine and to a loss of apparent repressi on by this amino acid. There is a fair correlation between the I-0.5 of hom ocitrate synthase for lysine, the intracellular lysine pool and the levels of Lys enzymes, confirming the importance of the activity control of the fi rst step of the pathway for the expression of LYS genes. The data are consi stent with the conclusion that inhibition by lysine of Lys14p activation re sults from the control of alpha AASA production through the feedback inhibi tion of homocitrate synthase activity.