Disease relevance of Acat1

• The primary structure of this enzyme was compared with those of four other thiolases (rat mitochondrial and peroxisomal 3-ketoacyl-CoA thiolases, acetoacetyl-CoA thiolase of Zoogloea ramigera, and cytosolic acetoacetyl-CoA thiolase of Saccharomyces uvarum) [1].

High impact information on Acat1

• Acetoacetyl-CoA thiolase partially exchanges 14C between C-1 and C-3 of acetoacetyl-CoA [2].
• The resulting 3-mercaptopropionyl-CoA is a poor substrate of acyl-CoA dehydrogenase but substitutes effectively for CoASH in reactions catalyzed by 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase [3].
• However, acetoacetyl-CoA thiolase was inactivated more rapidly than was respiration supported by acetoacetate [4].
• When the enzymes of beta-oxidation and ketone body degradation were assayed in mitochondria preincubated with 4-bromocrotonic acid, only 3-ketoacyl-CoA thiolase and acetoacetyl-CoA thiolase were found to be inactive [4].
• Preincubation of the 10,000 X g supernatant fraction of rat liver homogenates with PMSF (1 mM) resulted in a significant reduction of the activities of acetate thiokinase and 3-hydroxy-3-methylglutaric acid (HMG)-CoA synthase, but did not affect the activities of acetoacetyl-CoA thiolase [5].

Biological context of Acat1

• Molecular cloning and nucleotide sequence of cDNA encoding the entire precursor of rat mitochondrial acetoacetyl-CoA thiolase [1].
• The analysis of the initial-rate kinetics of the liver mitochondrial acetyl-CoA acetyltransferase (acetoacetyl-CoA thiolase) in the direction of acetoacetyl-CoA synthesis under product inhibition was performed [6].
• During pregnancy the synthesis of cholesterol and the activity of 3-hydroxy 3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase fell markedly before parturition; HMGCoA synthase activity was low during pregnancy and fell again immediately before delivery while acetoacetyl-CoA-thiolase was always low and constant [7].

Anatomical context of Acat1

• In addition to inhibiting isolated acetoacetyl-CoA thiolase, in hepatocytes the chloromethyl ketone derivatives of fatty acids also inhibited chloresterol synthesis, which uses this enzyme as an early step in the biosynthetic pathway [8].
• A 52 kDa protein could only be co-purified with the CoA-modified forms of acetyl-CoA acetyltransferase (acetoacetyl-CoA thiolase) (EC 2.3.1.9) from rat liver mitochondria [9].
• In contrast, we report, for the first time, the ready detection of mHS mRNA together with the mRNAs encoding the remaining enzymes of the 3-hydroxy-3-methylglutaryl-CoA cycle, namely, mitochondrial acetoacetyl-CoA thiolase and 3-hydroxy-3-methylglutaryl-CoA lyase, in primary cultures of neonatal meningeal fibroblasts [10].
• The enzymes studied are medium- and long-chain ATP-dependent acyl-CoA synthetases of the outer mitochondrial membrane and matrix, GTP-dependent acyl-CoA synthetase, carnitine acyltransferase, enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, general 3-oxoacyl-CoA thiolase and acetoacetyl-CoA thiolase [11].
• Identification, purification and characterization of an acetoacetyl-CoA thiolase from rat liver peroxisomes [12].

Associations of Acat1 with chemical compounds

• Acetoacetyl-CoA thiolase and 3-hydroxy-3-methylglutaryl coenzyme synthase which comprise the 3-hydroxy-3-methylglutaryl-CoA-generating system(s) for hepatic cholesterogenesis and ketogenesis exhibit dual mitochondrial and cytoplasmic localization [13].
• Preincubation of the 10,000 x g supernatant fraction of rat liver homogenates with cycloheximide (1 mM) caused a significant reduction in the levels of acetate thiokinase and hydroxymethylglutaryl-CoA synthase activities but not of acetoacetyl-CoA thiolase activity [14].
• Cytoplasmic acetoacetyl-CoA thiolase (acetyl-CoA C-acetyltransferase, EC 2.3.1.9) was partially purified from rat liver [15].
• Advantage was taken of the specific action of alk-3-ynoyl-CoA esters on acetoacetyl-CoA thiolase to show that in a postmitochondrial fraction from rat liver they are effective inhibitors of cholesterol synthesis from sodium [2-14C]acetate under conditions when mevalonate conversion into cholesterol and fatty acid synthesis are unafffected [15].
• Rat liver mitochondrial acetyl-CoA acetyltransferase (acetoacetyl-CoA thiolase, EC 2.3.1.9) exists additionally in the CoA-modified forms A1 and A2 [16].

Other interactions of Acat1

• 1. The effects of phenylalanine and its metabolites (phenylacetate, phenethylamine, phenyl-lactate, o-hydroxyphenylacetate and phenylpyruvate) on the activity of 3-hydroxybutyrate dehydrogenase (EC 1.1.1.30) 3-oxo acid CoA-transferase (EC 2.8.3.5) and acetoacetyl-CoA thiolase (EC 2.3.1.9) in brain of suckling rats were investigated [17].
• Stimulation of hepatic cholesterol biosynthesis by fatty acids. Effects of oleate on cytoplasmic acetoacetyl-CoA thiolase, acetoacetyl-CoA synthetase and hydroxymethylglutaryl-CoA synthase [18].
• Hydroxymethylglutaryl-coenzyme A (HMG-CoA) synthase is present in the mucosa of the proximal small intestine of the suckling rat, as are acetoacetyl-CoA thiolase and HMG-CoA lyase [19].

References