Reversible, coenzyme-A-mediated inactivation of biosynthetic condensing enzymes in yeast: a possible regulatory mechanism.
alpha-Isopropylmalate synthase [3-hydroxy-4-methyl-3-carboxyvalerate 2-oxo-3-methylbutyrate-lyase (CoA-acetylating); EC 4.1.3.12], the enzyme catalyzing the first committed step in leucine biosynthesis, and homocitrate synthase [3-hydroxy-3-carboxyadipate 2-oxoglutarate-lyase (CoA-acetylating); EC 4.1.3.21], the first enzyme in lysine biosynthesis in yeast, are rapidly inactivated in the presence of low concentrations of coenzyme A, a product of both reactions. Closely related compounds like 3-dephospho-coenzyme A or oxidized coenzyme A are almost without effect, as are other sulfhydryl compounds. Citrate (si)-synthase [citrate oxaloacetate-lyase (pro-3S-CH2-COO-minus leads to acetyl-CoA); EC 4.1.3.7] appears to be completely resistant against inactivation by coenzyme A. Inactivated alpha-isopropylmalate and homocitrate synthases can be reactivated by dialysis, but not by adding excess substrate. Protection against coenzyme-A-mediated inactivation is provided by relatively high concentrations of the alpha-ketoacid substrate or the specific end product inhibitor of each of the two enzymes. The coenzyme-A-mediated inactivation of alpha-isopropylmalate synthase has been more closely investigated. It requires the presence of divalent metal ions, with Zn++being most effective. The inactivation does not require molecular oxygen. It occurs in the presence of low concentrations of substrates and is observed in toluene-treated cells. These results, together with evidence that alpha-isopropylmalate synthase and homocitrate synthase are located in the mitochondria, suggest a mechanism by which increasing intra-mitochondrial coenzyme A concentrations might serve as a signal of decreasing acetyl-coenzyme A levels, triggering a temporary inactivation of biosynthetic acetyl-coenzyme A-consuming reactions in order to channel the available acetyl-coenzyme A into the citrate cycle.
D015079:2-Isopropylmalate Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors; D003065:Coenzyme A / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D013997:Time Factors
D002950:Citrate (si)-Synthase; D015079:2-Isopropylmalate Synthase; D007652:Oxo-Acid-Lyases; D003065:Coenzyme A