Disease relevance of acetyl-CoA

• A methylnickel intermediate in a bimetallic mechanism of acetyl-coenzyme A synthesis by anaerobic bacteria [1].
• Acetyl CoA levels, in the latter disease, were dramatically decreased, compared with both human controls and Reye syndrome patients [2].
• Expression of the ORF from pCWori(+) in Escherichia coli JM109 afforded a functional enzyme, as determined by (1)H-NMR and MS verification of the product baccatin III derived from 10-deacetylbaccatin III and acetyl CoA [3].
• Active acetyl-CoA synthase from Clostridium thermoaceticum obtained by cloning and heterologous expression of acsAB in Escherichia coli [4].
• In the bacterium Alcaligenes eutrophus, three genes encode the enzymes necessary to catalyze the synthesis of poly[(R)-(-)-3-hydroxybutyrate] (PHB) from acetyl-CoA [5].

Psychiatry related information on acetyl-CoA

• The concentration of substance P-like immunoreactive material (SPLI) and somatostatin-like immunoreactive material (SLI) and the activity of acetyl-CoA: choline-O-acetyltransferase (ChAT; EC 2.3.1.6) were measured in eight brain regions of 13 normal patients and 12 patients with Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT) [6].

High impact information on acetyl-CoA

• CLOCK shares homology with acetyl-coenzyme A binding motifs within the MYST family of HATs [7].
• The nature of the recognition of acetyl-lysine by the P/CAF bromodomain is similar to that of acetyl-CoA by histone acetyltransferase [8].
• Acetyl-CoA:alpha-glucosaminide N-acetyltransferase is a lysosomal-membrane enzyme deficient in a genetic disorder, Sanfilippo disease type C. The enzyme catalyzes the transfer of an acetyl group from cytoplasmic acetyl-coenzyme A (acetyl-CoA) to terminal alpha-glucosamine residues of heparan sulfate within the organelle [9].
• Acetylcholine synthesis in synaptosomes: mode of transfer of mitochondrial acetyl coenzyme A [10].
• In addition, the first atomic resolution structures of HATs have revealed conserved mechanisms of acetyl-CoA interaction among the superfamily of GNATs (Gcn5-related N-acetyltransferases) [11].

Chemical compound and disease context of acetyl-CoA

• Pyruvate formate-lyase (acetyl-CoA:formate C-acetyltransferase, EC 2.3.1.54) from anaerobic Escherichia coli cells converts pyruvate to acetyl-CoA and formate by a unique homolytic mechanism that involves a free radical harbored in the protein structure [12].
• Mucopolysaccharidosis IIIC (MPS IIIC, or Sanfilippo C syndrome) is a lysosomal storage disorder caused by the inherited deficiency of the lysosomal membrane enzyme acetyl-coenzyme A: alpha -glucosaminide N-acetyltransferase (N-acetyltransferase), which leads to impaired degradation of heparan sulfate [13].
• In Escherichia coli, acetyl phosphate can be formed from acetyl-CoA via the phosphotransacetylase (phosphate acetyltransferase; acetyl-CoA:orthophosphate acetyltransferase, EC 2.3.1.8) reaction and from acetate (plus ATP) via the acetate kinase (ATP:acetate phosphotransferase, EC 2.7.2.1) reaction [14].
• In this study, inhibition of FA synthesis at the physiologically regulated step of carboxylation of acetyl-CoA to malonyl-CoA by 5-(tetradecyloxy)-2-furoic acid (TOFA) was not cytotoxic to breast cancer cells in clonogenic assays [15].
• In contrast to E. coli PanK (bPanK), which is regulated by CoA and to a lesser extent by its thioesters, aPanK activity was selectively and potently inhibited by acetyl-CoA [16].

Biological context of acetyl-CoA

• Mutations in the conserved acetyl-CoA binding motif of Sas2p are shown to disrupt the ability of Sas2p to mediate the silencing at HML and telomeres, providing evidence for an important role for the acetyltransferase activity of the SAS complex in silencing [17].
• Nucleocytosolic acetyl-coenzyme a synthetase is required for histone acetylation and global transcription [18].
• Despite the diversity of substrate specificities, members of the GNAT superfamily demonstrate remarkable similarity in protein topology and mode of acetyl coenzyme A binding, likely reflecting a conserved catalytic mechanism [19].
• Activation of CB(1) in mice increases the hepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase (FAS) [20].
• Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2 [21].

Anatomical context of acetyl-CoA

• After exhaustive exercise, the skeletal muscle acetyl-CoA/CoASH ratio showed a linear correlation with the corresponding acetylcarnitine/free carnitine ratio [22].
• The contribution of lactate to acetyl-CoA was decreased in postischemic myocardium (with a significant increase in acetate), and anaplerosis was stimulated [23].
• Two pathways for the transport of acetyl-CoA to the mitochondria have been proposed [24].
• The acetyl-CoA produced has to be transported from the peroxisomes via the cytoplasm to the mitochondrial matrix in order to be degraded to CO(2) and H(2)O [24].
• The high level of PHB accumulation also suggests that the synthesis of plastid acetyl-CoA is regulated by a mechanism which responds to metabolic demand [5].

Associations of acetyl-CoA with other chemical compounds

• Malonyl-CoA, generated by acetyl-CoA carboxylases 1 and 2 (Acc1 and Acc2), is a key regulator of both mitochondrial fatty acid oxidation and fat synthesis [21].
• The first involves peroxisomal conversion of acetyl-CoA into glyoxylate cycle intermediates followed by transport of these intermediates to the mitochondria [24].
• Using a selective screen, we have isolated several mutants that are specifically affected in the second pathway, the carnitine-dependent acetyl-CoA transport from the peroxisomes to the mitochondria, and assigned these CDAT mutants to three different complementation groups [24].
• The facB gene is required for acetate induction of acetamidase (amdS) and the acetate utilization enzymes acetyl-CoA synthase (facA), isocitrate lyase (acuD) and malate synthase (acuE) in Aspergillus nidulans [25].
• To elucidate the mechanism of betaA-induced neuronal death, we searched for substrates of TPKI/GSK-3beta in a two-hybrid system and identified pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA in mitochondria [26].

Gene context of acetyl-CoA

• We report that mutants with conditional defects in the rate-limiting enzyme of fatty acid synthesis, acetyl coenzyme A carboxylase (ACC1), display unusually multilobed vacuoles, similar to those observed in vac8 mutant cells [27].
• Inhibition of acetyl coenzyme A carboxylase activity restores expression of the INO1 gene in a snf1 mutant strain of Saccharomyces cerevisiae [28].
• We identified mutations in ACC1 and FAS1, two genes important for fatty acid biosynthesis in yeast; ACC1 encodes acetyl coenzyme A carboxylase (Acc1), and FAS1 encodes the beta subunit of fatty acid synthase [28].
• Furthermore, we demonstrate that STAGA has acetyl coenzyme A-dependent transcriptional coactivator functions from a chromatin-assembled template in vitro and associates in HeLa cells with spliceosome-associated protein 130 (SAP130) and DDB1, two structurally related proteins [29].
• Taken together, these inhibition patterns support an ordered BiBi kinetic mechanism for PCAF in which acetyl-CoA binding precedes H3-20 binding [30].

Analytical, diagnostic and therapeutic context of acetyl-CoA

• Recovery of cardiac work, O2 consumption (MVO2), and rates of acetyl-coenzyme A and ATP production during reperfusion were determined [31].
• Electrophoretic mobility shift assays and DNase I footprinting revealed that acetyl-CoA increased the affinity of the general transcription factor TFIID for promoter DNA in a TBP-associated factor (TAF)-dependent manner [32].
• The assay was based on the separation and detection of N-[(3)H]acetylarylethylamine formed from various arylethylamines and tritiated acetyl-CoA, by means of high performance liquid chromatography with radiochemical detection [33].
• However, conditions of perfusion that increased acetyl-CoA supply resulted in higher turnover and concentration, demonstrating that malonyl-CoA turnover is regulated by the supply of acetyl-CoA [34].
• No flavin semiquinone was observed during potentiometric titrations; however, low amounts of the radical were observed when Isf was quickly frozen after reaction with CO and the CO dehydrogenase/acetyl-CoA synthase complex from M. thermophila [35].

References