Acetaldehyde dehydrogenase

Formally, in redox reactions there is transfer of electrons from a donor (the reductant) to the acceptor (the oxidant), forming a redox couple or pair. Oxidations in biological systems are often reactions in which hydrogen is removed from a compound or in which oxygen is added to a compound. An example is the oxidation of ethanol to acetaldehyde and then to acetic acid where the oxidant is NAD. catalyzed by alcohol dehydrogenase and acetaldehyde dehydrogenase, respectively. 

Alcohol metabolism (Figure 6.37) occurs mainly through oxidative pathways involving the enzymes alcohol dehydrogenase (ADH), acetaldehyde dehydrogenase (ALDH),... 

The retention of 1,2-dibromoethane in tissues and body fluids can be altered by concurrent exposure to modifiers of enzyme activity, such as disulfiram (Plotnick et al. 1979). The concentration of radiolabeled 1,2-dibromoethane in the liver, kidneys, spleen, testes, and brain increased significantly in rats fed disulfiram in the diet for 12 days before an oral dose of 15 mg C-1,2- dibromoethane/kg compared with rats not fed disulfiram. Disulfiram, an inhibitor of P-450 metabolism (via action on acetaldehyde dehydrogenase), was found to increase the uptake of C into liver nuclei. These observations correlate well with the results of chronic studies (Wong et al. 1982) that demonstrated enhanced tumorigenic effects in the liver and testes following combined 1,2-dibromoethane and disulfiram exposure. 

Alcoholics are very susceptible to hypoglycemia. In addition to poor nutrition and the fact that alcohol is metaboUzed to acetate (acetyl CoA), the high amounts of cytoplasmic NADH formed by alcohol dehydrogenase and acetaldehyde dehydrogenase interfere with gluconeogenesis. High NADH favors the formation ofi... 

Figure 3.4 Structures of (a) coprin, (b) cyclopropanone, and (c) the thio-hemiketal of cyclopropanone formed at the essential SH-group of acetaldehyde dehydrogenase that blocks the activity of the enzyme.

Most of the alcohol distributes into body water, but like most solvents and anesthetics some distributes into fat. It is excreted in the urine and breath, hence the utility of taking breath samples to evaluate alcohol exposure. The majority of alcohol is metabolized in the liver. Alcohol dehydrogenase (ADH) metabolizes alcohol to acetaldehyde. Acetaldehyde is toxic, with elevated levels causing flushing, headache, nausea, and vomiting. Acetaldehyde is in turn quickly metabolized to the less toxic acetate by acetaldehyde dehydrogenase (ALDH) (Figure 3.1). 

The answer is D. Many Asians lack a low-AJjj form of acetaldehyde dehydrogenase, which is responsible for detoxifying acetaldehyde generated by oxidation of ethanol in the liver. Acetaldehyde accumulation in the blood of such individuals leads to the facial flushing and neurologic effects exhibited by the man of Japanese descent. 

Harada S, Agarwal DP, Goedde HW. Isozyme variations in acetaldehyde dehydrogenase (EC1.2.1.3.) in human tissues. Hum Genet 1978 44 181-185. 

Disulfiram is an aversive therapy that works by inhibiting acetaldehyde dehydrogenase. Interactions between disulfiram and alcohol can result in potentially severe reactions, such as myocardial infarction, congestive heart failure, respiratory depression and death. Patients taking disulfiram should be warned of the possible presence of alcohol in liquid medicines, tonics, foods and even in toiletries and mouthwashes. Patient adherence to disulfiram is poor and there is a lack of strong evidence for its effectiveness, thus it is not routinely recommended. 

Alcohol intake depletes the cellular supply of NAD (because of the alcohol and acetaldehyde dehydrogenase reactions) and consequently the NAD NADH ratio falls. Reactions that depend on NAD+ will thus be curtailed ... 

Meaden, P. G., Dickinson, F. M., Mifsud, A., Tessier, W., Westwater, J., Bussey, H., Midgley, M. (1997) The ALD6 gene of Saccharomyces cerevisiae encodes a cytosolic, Mg -activated acetaldehyde dehydrogenase. Yeast, 13, 1319-1327. 

Normally, the acetaldehyde, which is the cause of the symptoms when present at high concentrations, is processed to acetate by acetaldehyde dehydrogenase. 

Most people have two forms of the acetaldehyde dehydrogenase, a low K jyi mitochondrial form and a high K jy[ cytosolic form. In susceptible persons, the mitochondrial enzyme is less active due to the substitution of a single amino acid, and acetaldehyde is processed only by the cytosolic enzyme. Because this enzyme has a high K ]y[, less acetaldehyde is converted into acetate excess acetaldehyde escapes into the blood and accounts for the physiological effects. 

Some aminocyclopropanes show biochemical activities. In some cases this is due to reactions of the three-membered ring (e.g. inhibition of acetaldehyde dehydrogenase by 4,... 

Coprine (506) was isolated from the inky cap mushroom Coprinus atramentarius 416,613 mushroom proved to be non-toxic generally, but it caused severe illness when taken together with alcohol. It was found that semiaminal 4, the product of hydrolysis of 506, was the active substance inhibiting acetaldehyde dehydrogenase 61 -624... 

The conversion of ethanol to acetic acid, by sequential action of the ethanol-oxidizing system of the ER and acetaldehyde dehydrogenase, is shown in Figure 4.70. The conversion of acetic acid to a cetyl-Co A, as catalyzed by thiokinase, is shown in Figure 4,71. Thiokinase accepts short-chain fatty acids, as well as acetic acid, as its substrate. Acetj l-CoA is a substrate of the Krebs cycle. 

Racial differences could be a factor in the high incidence of delayed skin reactions to contrast media in Japan, as 43% of Japanese are deficient in acetaldehyde dehydrogenase. This deficiency results in the accumulation of acetaldehyde, which potentiates the ability of contrast agents (especially dimers), to bridge proteins, which is a probable causative factor in many of their adverse effects (11). 

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