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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
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discounted EARLY registration ends Dec 31, 2014
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MetaCyc Pathway: oxidative ethanol degradation III

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 Inferred from experiment Inferred by computational analysis

Expected Taxonomic Range: Metazoa

Summary:
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 [Salway04a]. 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 [Salway04a]. 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].

Variants: ethanol degradation I , ethanol degradation II , ethanol degradation IV


References

Best03: Best CA, Laposata M (2003). "Fatty acid ethyl esters: toxic non-oxidative metabolites of ethanol and markers of ethanol intake." Front Biosci 8;e202-17. PMID: 12456329

Bosron: Bosron WF, Li TK "Genetic polymorphism of human liver alcohol and aldehyde dehydrogenases, and their relationship to alcohol metabolism and alcoholism." Hepatology 6(3);502-10. PMID: 3519419

Chrostek03: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the human pancreas." Dig Dis Sci 48(7);1230-3. PMID: 12870777

Salway04a: Salway, J.G., Granner, D.K. (2004). "Metabolism at a Glance, Second Edition." Blackwell Publishing, ISBN:1405107162.

Waluga03: Waluga M, Hartleb M (2003). "[Alcoholic liver disease]." Wiad Lek 56(1-2);61-70. PMID: 12901271

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

Yamashita01: Yamashita H, Kaneyuki T, Tagawa K (2001). "Production of acetate in the liver and its utilization in peripheral tissues." Biochim Biophys Acta 1532(1-2);79-87. PMID: 11420176

Other References Related to Enzymes, Genes, Subpathways, and Substrates of this Pathway

Agarwal87: Agarwal DP, Goedde HW (1987). "Human aldehyde dehydrogenase isozymes and alcohol sensitivity." Isozymes Curr Top Biol Med Res 16;21-48. PMID: 3610592

Asai96: Asai H, Imaoka S, Kuroki T, Monna T, Funae Y (1996). "Microsomal ethanol oxidizing system activity by human hepatic cytochrome P450s." J Pharmacol Exp Ther 277(2);1004-9. PMID: 8627510

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

Barak04: 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

Brown77: Brown TD, Jones-Mortimer MC, Kornberg HL (1977). "The enzymic interconversion of acetate and acetyl-coenzyme A in Escherichia coli." J Gen Microbiol 1977;102(2);327-36. PMID: 21941

Chang97a: Chang C, Yoshida A (1997). "Human fatty aldehyde dehydrogenase gene (ALDH10): organization and tissue-dependent expression." Genomics 40(1);80-5. PMID: 9070922

Coon87: Coon MJ, Koop DR (1987). "Alcohol-inducible cytochrome P-450 (P-450ALC)." Arch Toxicol 60(1-3);16-21. PMID: 3304205

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

Harada01: Harada S (2001). "[Classification of alcohol metabolizing enzymes and polymorphisms--specificity in Japanese]." Nihon Arukoru Yakubutsu Igakkai Zasshi 36(2);85-106. PMID: 11398342

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

Hu97a: 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

Ioannides04: Ioannides C, Lewis DF (2004). "Cytochromes P450 in the bioactivation of chemicals." Curr Top Med Chem 4(16);1767-88. PMID: 15579107

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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Report Errors or Provide Feedback
Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
Page generated by SRI International Pathway Tools version 18.5 on Mon Dec 22, 2014, biocyc11.