Disease relevance of coenzyme A

• The alpha-ketoglutarate dehydrogenase complex from Escherichia coli catalyzes the hydrolysis of S-succinyl-CoA to succinate and CoASH [1].
• A prerequisite for this reaction is the promiscuity of the Bacillus subtilis phosphopantetheinyl transferase Sfp for loading chemically synthesized peptidyl-coenzyme A substrates instead of the smaller natural substrate coenzyme A (CoASH) onto apoPCP [2].
• Fasting for 24 or 48 h did not affect lung CoASH levels or lung weights, despite 6 and 12% losses in body weight [3].
• Therefore, the acetyl-CoA/CoASH ratios in facultatively anaerobic bacteria were 10 times higher than those in aerobic bacteria [4].
• Pulmonary edema was observed in the hyperoxic rats and accounted for some of the declines in CoASH concentrations, but CoASH contents per total lung also declined [5].

High impact information on coenzyme A

• Lack of regulation of enzyme activity by free CoASH suggests that PTE-Ia and PTE-Ic regulate intraperoxisomal levels of acyl-CoA, and they may have a function in termination of beta-oxidation of fatty acids of different chain lengths [6].
• The uptake of fatty acid in the presence of non-limiting amounts of ATP and CoASH was dependent on the amount of endogenous fatty acyl-CoA synthetase either retained within vesicles during isolation or trapped within vesicles after isolation by freeze-thawing [7].
• When CoASH and ATP were present there was also a linear accumulation of acyl-CoA thioesters (plus derived polar lipids), with no measurable lag phase (<30 s), indicating that the FFA pool supplying LACS rapidly reached steady state [8].
• PTE-2 activity is inhibited by free CoASH, suggesting that intraperoxisomal free CoASH levels regulate the activity of this enzyme [9].
• To prevent CoASH sequestration and to facilitate excretion of chain-shortened carboxylic acids, acyl-CoA thioesterases, which catalyze the hydrolysis of acyl-CoAs to the free acid and CoASH, may play important roles [9].

Chemical compound and disease context of coenzyme A

• The key step of the pathway, the dehydration of (R)-lactate required acetyl phosphate and CoASH under anaerobic conditions [10].
• In Escherichia coli K-12 cells, the addition of reagents to inhibit the respiratory system led to a rapid decrease in the amount of acetyl-CoA with a concomitant increase in the amount of CoASH, whereas the addition of cerulenin, a specific inhibitor of fatty acid synthase, triggered the intracellular accumulation of malonyl-CoA [4].
• As carnitine conjugation is thought to be the only detoxification metabolic route in canine muscle, under certain circumstances such as carnitine deficiency, the risk of exposure with toxic pivaloyl CoA might increase and the CoASH pool in canine muscle might be exhausted, resulting in toxicity in canine muscle [11].

Biological context of coenzyme A

• Inhibition by CoA thioesters was not due to their hydrolysis to CoASH [12].
• Long-chain acyl-CoA thioesterases hydrolyze long-chain acyl-CoAs to the corresponding free fatty acid and CoASH and may therefore play important roles in regulation of lipid metabolism [13].
• As such, we advance the hypothesis that the selection of substrate for condensation with CoASH and subsequent oxidation in the tricarboxylic acid cycle is regulated kinetically through the Km values of the appropriate condensation enzymes and through the absolute levels of free CoASH in the mitochondria [14].
• Valyl-tRNA synthetase catalyzes aminoacylations of CoA-SH with valine, threonine, alanine, serine, and isoleucine [15].
• Post-translational modification with Sfp and CoASH introduced the HS-pantP prosthetic group to the apo-PCP, enabling subsequent loading with L-cysteine to generate the Cys-S-PCP acyl enzyme intermediate [16].

Anatomical context of coenzyme A

• Addition of recombinant PTE-2 to incubations containing isolated mouse liver peroxisomes strongly inhibited bile acid-CoA:amino acid N-acyltransferase activity, suggesting that this thioesterase can interfere with CoASH-dependent pathways [9].
• When liver and skeletal muscle mitochondria were exposed to DNP-Et in the presence of ATP and CoASH, the DNP-Et-CoA formed completely inhibited liver CPT I while leaving the muscle enzyme unaffected [17].
• Bile acid: CoASH ligases from guinea pig and porcine liver microsomes. Purification and characterization [18].
• A study of the activation of valproic acid (2-n-propylpentanoic acid) by a soluble extract of rat liver mitochondria in the presence of ATP, CoASH, and MgCl2 revealed that, in addition to valproyl-CoA, an unknown UV-absorbing compound is formed which is the sole product when CoASH is omitted from the incubation mixture [19].
• In the mouse myocardium, DNP decreased the intracellular ATP and ADP levels, without affecting either acyl-CoA synthetase activity or the level of CoA-SH [20].

Associations of coenzyme A with other chemical compounds

• An azido-125I-CoA photolabel was synthesized from N-(3-iodo-[125I]4-azidophenylpropionamido)cysteinyl- 5-(2'thiopyridyl) cysteine ([125I]ACTP) and CoASH, separated by chromatography on a silica gel TLC, and identified by autoradiography [21].
• Lysyl-tRNA synthetase aminoacylates CoA-SH with lysine, leucine, threonine, alanine, valine, and isoleucine [15].
• For comparison, the equilibrium constant for the reaction CoASH + GSSG in equilibrium CoASSG + GSH was found to be 3.1 at pH 8 [22].
• HoPan triggered significant changes in hepatic gene expression that substantially increased the thioesterases, which liberate CoASH from acyl-CoA, and increased pyruvate dehydrogenase kinase 1, which prevents the conversion of CoASH to acetyl-CoA [23].
• These results identify the metabolic rearrangements that maintain the CoASH pool which is critical to mitochondrial functions, including gluconeogenesis, fatty acid oxidation, and the tricarboxylic acid and urea cycles [23].

Gene context of coenzyme A

• The apo-PCP fragment was covalently modified to phosphopantetheinylated holo-PCP by pure Lys5 and CoASH with a Km of 1 microM and kcat of 3 min-1 for both the PCP and CoASH substrates [24].
• In this study, mechanistic aspects of the AANAT-catalyzed alkyl transfer reaction were explored by employing CoASH and a series of N-haloacetyltryptamines that were also evaluated for their AANAT acetyltransferase inhibitory activities [25].
• Neither oleoyl CoA, oleic acid, nor CoASH altered overall I-FABP rotational correlation time [26].
• Further, ligands such as fatty acids, fatty acyl CoAs, and/or CoASH differentially modulate the I-FABP and L-FABP dynamics, and the ligand binding sites of these proteins differ in their ability to order the ligands [26].
• Brain acyl-CoA hydrolase (BACH) hydrolyzes long-chain acyl-CoAs to free fatty acids and CoA-SH [27].

Analytical, diagnostic and therapeutic context of coenzyme A

• A high sensitivity high performance liquid chromatography method was used to measure malonyl, succinyl, beta-hydroxy beta-methylglutaryl and acetyl-CoA esters and free CoASH [28].
• After the preincubation period, liver or fibroblast homogenate is added plus CoASH, and the production of choloyl-CoA is determined by HPLC [29].
• Lipid-metabolizing enzymes, CoASH and long-chain acyl-CoA in rat liver after treatment with tiadenol, nicotinic acid and niadenate [30].
• This change in the isoelectric focusing band pattern after interaction of the subunits with CoASH in interpreted as being the result of an apparently covalent secondary modification of the protein side chains [31].
• After specific adhesion via the appropriate carbohydrate, CoASH is apparently released from cells and undergoes disulfide exchange with the cleavable immobilization linker we used to tether the sugars to the artificial surfaces [32].

References