[THIL_HUMAN] Defects in ACAT1 are a cause of 3-ketothiolase deficiency (3KTD) [MIM:203750]; also known as alpha-methylacetoaceticaciduria. 3KTD is an inborn error of isoleucine catabolism characterized by intermittent ketoacidotic attacks associated with unconsciousness. Some patients die during an attack or are mentally retarded. Urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, triglylglycine, butanone is increased. It seems likely that the severity of this disease correlates better with the environmental or acquired factors than with the ACAT1 genotype.
[THIL_HUMAN] Plays a major role in ketone body metabolism.
Thiolases are CoA-dependent enzymes which catalyze the formation of a carbon-carbon bond in a Claisen condensation step and its reverse reaction via a thiolytic degradation mechanism. Mitochondrial acetoacetyl-coenzyme A (CoA) thiolase (T2) is important in the pathways for the synthesis and degradation of ketone bodies as well as for the degradation of 2-methylacetoacetyl-CoA. Human T2 deficiency has been identified in more than 60 patients. A unique property of T2 is its activation by potassium ions. High-resolution human T2 crystal structures are reported for the apo form and the CoA complex, with and without a bound potassium ion. The potassium ion is bound near the CoA binding site and the catalytic site. Binding of the potassium ion at this low-affinity binding site causes the rigidification of a CoA binding loop and an active site loop. Unexpectedly, a high-affinity binding site for a chloride ion has also been identified. The chloride ion is copurified, and its binding site is at the dimer interface, near two catalytic loops. A unique property of T2 is its ability to use 2-methyl-branched acetoacetyl-CoA as a substrate, whereas the other structurally characterized thiolases cannot utilize the 2-methylated compounds. The kinetic measurements show that T2 can degrade acetoacetyl-CoA and 2-methylacetoacetyl-CoA with similar catalytic efficiencies. For both substrates, the turnover numbers increase approximately 3-fold when the potassium ion concentration is increased from 0 to 40 mM KCl. The structural analysis of the active site of T2 indicates that the Phe325-Pro326 dipeptide near the catalytic cavity is responsible for the exclusive 2-methyl-branched substrate specificity.
Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function.,Haapalainen AM, Merilainen G, Pirila PL, Kondo N, Fukao T, Wierenga RK Biochemistry. 2007 Apr 10;46(14):4305-21. Epub 2007 Mar 20. PMID:17371050
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
↑ Fukao T, Yamaguchi S, Orii T, Schutgens RB, Osumi T, Hashimoto T. Identification of three mutant alleles of the gene for mitochondrial acetoacetyl-coenzyme A thiolase. A complete analysis of two generations of a family with 3-ketothiolase deficiency. J Clin Invest. 1992 Feb;89(2):474-9. PMID:1346617 doi:http://dx.doi.org/10.1172/JCI115608
↑ Fukao T, Yamaguchi S, Tomatsu S, Orii T, Frauendienst-Egger G, Schrod L, Osumi T, Hashimoto T. Evidence for a structural mutation (347Ala to Thr) in a German family with 3-ketothiolase deficiency. Biochem Biophys Res Commun. 1991 Aug 30;179(1):124-9. PMID:1715688
↑ Wakazono A, Fukao T, Yamaguchi S, Hori T, Orii T, Lambert M, Mitchell GA, Lee GW, Hashimoto T. Molecular, biochemical, and clinical characterization of mitochondrial acetoacetyl-coenzyme A thiolase deficiency in two further patients. Hum Mutat. 1995;5(1):34-42. PMID:7728148 doi:http://dx.doi.org/10.1002/humu.1380050105
↑ Haapalainen AM, Merilainen G, Pirila PL, Kondo N, Fukao T, Wierenga RK. Crystallographic and kinetic studies of human mitochondrial acetoacetyl-CoA thiolase: the importance of potassium and chloride ions for its structure and function. Biochemistry. 2007 Apr 10;46(14):4305-21. Epub 2007 Mar 20. PMID:17371050 doi:10.1021/bi6026192