title: Differential effects of 2-oxo acids on pyruvate utilization and fatty acid synthesis in rat brain.
abstract: 1. The effects of 2-oxo-4-methylpentanoate, 2-oxo-3-methylbutanoate and 2-oxo-3-methylpentanoate on the activity of pyruvate dehydrogenase (EC 1.2.4.1), citrate synthase (EC 4.1.3.7), acetyl-CoA carboxylase, (EC 6.4.1.2) and fatty acid synthetase derived from the brains of 14-day-old rats were investigated. 2. The pyruvate dehydrogenase enzyme activity was competitively inhibited by 2-oxo-3-methylbutanoate with respect to pyruvate with a K(i) of 2.04mm but was unaffected by 2-oxo-4-methylpentanoate or 2-oxo-3-methylpentanoate. 3. The citrate synthase activity was inhibited competitively (with respect to acetyl-CoA) by 2-oxo-4-methylpentanoate (K(i)~7.2mm) and 2-oxo-3-methylbutanoate (K(i)~14.9mm) but not by 2-oxo-3-methylpentanoate. 4. The acetyl-CoA carboxylase activity was not inhibited significantly by any of the 2-oxo acids investigated. 5. The fatty acid synthetase activity was competitively inhibited (with respect to acetyl-CoA) by 2-oxo-4-methylpentanoate (K(i)~930mum) and 2-oxo-3-methylpentanoate (K(i)~3.45mm) but not by 2-oxo-3-methylbutanoate. 6. Preliminary experiments indicate that 2-oxo-4-methylpentanoate and 2-oxo-3-phenylpropionate (phenylpyruvate) significantly inhibit the ability of intact brain mitochondria from 14-day-old rats to oxidize pyruvate. 7. The results are discussed with reference to phenylketonuria and maple-syrup-urine disease. A biochemical mechanism is proposed to explain the characteristics of these diseases.
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002950:Citrate (si)-Synthase / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005227:Fatty Acids / Q000096:biosynthesis*; D007651:Keto Acids / Q000494:pharmacology*; D007700:Kinetics; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism*; D051381:Rats
chemical_list: D005227:Fatty Acids; D007651:Keto Acids; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D064429:Fatty Acid Synthases; D002950:Citrate (si)-Synthase; D000103:Acetyl-CoA Carboxylase