Inhibitors of metabolic reactions. Scope and limitation of acyl-CoA-analogue CoA-thioethers.
Substrate and intermediate analogue inhibitors of enzymes were prepared in which the thioester oxygen of acyl-CoA substrates is replaced by hydrogen with formation of CoA-thioethers. Experiments performed with ATP citrate lyase and S-(3,4-dicarboxy-3-hydroxybutyl)-CoA are consistent with citryl-CoA but not with citryl-enzyme being the direct precursor of the products acetyl-CoA and oxaloacetate. Consistent with these results, a previously described isotopic exchange between acetyl-CoA and [3H]CoASH, indicating the formation of an acetyl-enzyme in the reaction pathway, could not be confirmed. Substrate analogue CoA-thioethers of malate synthase are inhibitors endowed with the affinity of the substrates. Acetyl carboxylase and fatty acid synthetase are not inhibited by the substrate analogue S-ethyl-CoA; S-carboxyethyl-CoA, which could substitute for malonyl-CoA, is likewise not inhibitory. An explanation is proposed. Previously suggested roles of S-carboxymethyl-CoA, an acetyl-CoA-related inhibitor of citrate synthase, are discussed in the light of new experimental data. S-Acetyl, S-propionyl and S-carboxymethyl derivatives of 1,N6-etheno-CoA loose the high affinity of their CoA-counterparts to citrate synthase, probably because the ethylene group prevents proper binding to the enzyme.
Institut für Physiologische Chemie, Technischen Universität München, Federal Republic of Germany.
U
U
Lill
A
A
Kollmann-Koch
A
A
Bibinger
H
H
Eggerer
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors*; D000214:Acyl Coenzyme A / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D002950:Citrate (si)-Synthase / Q000037:antagonists & inhibitors; D064429:Fatty Acid Synthases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D012441:Saccharomyces cerevisiae / Q000201:enzymology; D013440:Sulfides / Q000138:chemical synthesis / Q000494:pharmacology*
D000214:Acyl Coenzyme A; D013440:Sulfides; D000105:Acetyl Coenzyme A; D064429:Fatty Acid Synthases; D002950:Citrate (si)-Synthase; D001275:ATP Citrate (pro-S)-Lyase; D000103:Acetyl-CoA Carboxylase