This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
|Superclasses:||Degradation/Utilization/Assimilation → Alcohols Degradation → Ethanol Degradation|
Some taxa known to possess this pathway include : Homo sapiens
Expected Taxonomic Range: Metazoa
This ethanol degradation pathway begins with conversion of ethanol to acetaldehyde by the endoplasmic reticulum (ER) Microsomal Ethanol Oxidising System (MEOS), also known as cytochrome P-450 2E1 [Salway04b]. The resulting acetaldehyde leaves the ER to the cytoplasm and then passes into the mitochondrial compartment where it is converted to acetate (by mitochondrial aldehyde dehydrogenase). Should acetate be activated to acetyl-CoA within the liver, it would not be oxidized by the Krebs cycle because of the prevailing high ratio of NADH + H / NAD+ within the liver mitochondrial matrix. Consequently, acetate leaves the mitochondrial compartment and the hepatocyte to be metabolized by extra-hepatic tissues [Salway04b]. Extrahepatic tissues take up acetate where it is converted to acetyl-CoA [Yamashita01].
Four distinct human ethanol degradation pathways have been described - three oxidative pathways and one nonoxidative pathway. All oxidative pathways mediate the oxidation of ethanol to acetaldehye which is then oxidized to acetate for subsequent extra-hepatic activation to acetyl-CoA [Yamashita01]. Oxidative pathways are differentiated based on the enzyme/mechanism by which ethanol is oxidized to acetaldehyde. The present pathway utilizes the endoplasmic reticulum MEOS, also known as cytochrome P-450 2E1, with the other two oxidative pathways utilizing cytoplasmic alcohol dehydrogenase (ethanol degradation II) and peroxisomal catalase (ethanol degradation IV), respectively. The nonoxidative pathway is less well characterized but produces fatty acid ethyl esters (FAEEs) as primary end products [Best03].
Oxidative and nonoxidative pathways have been demonstrated in a range of tissues including gastric, pancreatic, hepatic and lung. Inhibition of oxidative ethanol degradation pathways raises both hepatic and pancreatic FAEE levels demonstrating that oxidative and nonoxidative pathways are alternative metabolically linked pathways. Pancreatic ethanol metabolism occurs predominantly by the nonoxidative pathway but oxidative routes to acetaldehyde have also been demonstrated in the pancreas - the cytochrome P450 2E1 & alcohol dehydrogenase pathways [Chrostek03].
Ethanol metabolism occurs predominantly in the liver and the resulting oxidative metabolite acetaldehyde is thought to play a role in alcohol induced liver injury. Additionally, there is now solid evidence that FAEEs also play a role in alcoholic pancreatitis [Werner02a]. Blood and organ levels of FAEEs are raised by ethanol consumption with the highest concentration observed in the pancreas. FAEE generation from ethanol is greater in the pancreas than in any other organ suggesting that the pancreatic pathway contributes to raised blood and organ FAEE levels [Werner02a].
Under conditions of acute ethanol consumption, the majority of ethanol is degraded by the hepatic oxidative pathways predominantly the alcohol dehydrogenase mediated pathway. However, under conditions of chronic ethanol consumption, hepatic MEOS activity and nonoxidative pathways are induced and quantitatively make a greater contribution to ethanol catabolism. The stimulatory effect of ethanol on Cytochrome P450 2E1 levels results in increased oxygen consumption, production of excess free radicals and increased metabolism of ethanol, vitamin A and testosterone - the chronic effects of which contribute to depletion of antioxidative activity. Antioxidative deficiency (glutathione, vitamin E, phosphatidylcholine) and excess free radicals are believed to subsequently contribute to the progression of alcoholic liver disease [Waluga03].
Polymorphic loci for genes encoding enzymes of ethanol degradation pathways have been identified and resulting variant isoenzymes characterized and found to exhibit distinct kinetic properties. Indeed, genetically determined differences in ethanol metabolism may, in part, account for the variability of individual susceptibility to the physical complications of alcohol abuse [Bosron].
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Werner02a: Werner J, Saghir M, Warshaw AL, Lewandrowski KB, Laposata M, Iozzo RV, Carter EA, Schatz RJ, Fernandez-Del Castillo C (2002). "Alcoholic pancreatitis in rats: injury from nonoxidative metabolites of ethanol." Am J Physiol Gastrointest Liver Physiol 283(1);G65-73. PMID: 12065293
Ashibe07: Ashibe B, Hirai T, Higashi K, Sekimizu K, Motojima K (2007). "Dual subcellular localization in the endoplasmic reticulum and peroxisomes and a vital role in protecting against oxidative stress of fatty aldehyde dehydrogenase are achieved by alternative splicing." J Biol Chem 282(28);20763-73. PMID: 17510064
Barak04a: Barak R, Prasad K, Shainskaya A, Wolfe AJ, Eisenbach M (2004). "Acetylation of the chemotaxis response regulator CheY by acetyl-CoA synthetase purified from Escherichia coli." J Mol Biol 342(2);383-401. PMID: 15327942
Braun87: Braun T, Bober E, Singh S, Agarwal DP, Goedde HW (1987). "Evidence for a signal peptide at the amino-terminal end of human mitochondrial aldehyde dehydrogenase." FEBS Lett 215(2);233-6. PMID: 3582651
De96a: De Laurenzi V, Rogers GR, Hamrock DJ, Marekov LN, Steinert PM, Compton JG, Markova N, Rizzo WB (1996). "Sjogren-Larsson syndrome is caused by mutations in the fatty aldehyde dehydrogenase gene." Nat Genet 12(1);52-7. PMID: 8528251
Fairbrother98: Fairbrother KS, Grove J, de Waziers I, Steimel DT, Day CP, Crespi CL, Daly AK (1998). "Detection and characterization of novel polymorphisms in the CYP2E1 gene." Pharmacogenetics 8(6);543-52. PMID: 9918138
Felux13: Felux AK, Denger K, Weiss M, Cook AM, Schleheck D (2013). "Paracoccus denitrificans PD1222 utilizes hypotaurine via transamination followed by spontaneous desulfination to yield acetaldehyde and, finally, acetate for growth." J Bacteriol 195(12);2921-30. PMID: 23603744
Gillam94: Gillam EM, Guo Z, Guengerich FP (1994). "Expression of modified human cytochrome P450 2E1 in Escherichia coli, purification, and spectral and catalytic properties." Arch Biochem Biophys 312(1);59-66. PMID: 8031147
Hempel85: Hempel J, Kaiser R, Jornvall H (1985). "Mitochondrial aldehyde dehydrogenase from human liver. Primary structure, differences in relation to the cytosolic enzyme, and functional correlations." Eur J Biochem 153(1);13-28. PMID: 4065146
Hu97: Hu Y, Oscarson M, Johansson I, Yue QY, Dahl ML, Tabone M, Arinco S, Albano E, Ingelman-Sundberg M (1997). "Genetic polymorphism of human CYP2E1: characterization of two variant alleles." Mol Pharmacol 51(3);370-6. PMID: 9058590
Kikonyogo96: Kikonyogo A, Pietruszko R (1996). "Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution." Biochem J 316 ( Pt 1);317-24. PMID: 8645224
Kumari95: Kumari S, Tishel R, Eisenbach M, Wolfe AJ (1995). "Cloning, characterization, and functional expression of acs, the gene which encodes acetyl coenzyme A synthetase in Escherichia coli." J Bacteriol 1995;177(10);2878-86. PMID: 7751300
Kurys89: Kurys G, Ambroziak W, Pietruszko R (1989). "Human aldehyde dehydrogenase. Purification and characterization of a third isozyme with low Km for gamma-aminobutyraldehyde." J Biol Chem 264(8);4715-21. PMID: 2925663
Kurys93: Kurys G, Shah PC, Kikonygo A, Reed D, Ambroziak W, Pietruszko R (1993). "Human aldehyde dehydrogenase. cDNA cloning and primary structure of the enzyme that catalyzes dehydrogenation of 4-aminobutyraldehyde." Eur J Biochem 218(2);311-20. PMID: 8269919
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