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MetaCyc Pathway: ethanol degradation II

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: Archaea , Bacteria , Eukaryota

Summary:
This ethanol degradation pathway begins with conversion of ethanol to acetaldehyde by cytosolic alcohol dehydrogenase. The resulting acetaldehyde 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 metabolised by extra-hepatic tissues [Salway04]. 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 cytoplasmic alcohol dehydrogenase with the other two oxidative pathways utilizing endoplasmic reticulum Microsomal Ethanol Oxidizing System (MEOS) (oxidative ethanol degradation III) and peroxisomal catalase (ethanol degradation IV), respectively. MEOS is also known as Cytochrome P450 2E1. 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 [Werner02]. 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 [Werner02].

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 IV , oxidative ethanol degradation III

Credits:
Created 16-Aug-2004 by Wagg J , SRI International


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

Salway04: 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

Werner02: 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

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

Bindschedler05: Bindschedler LV, Wheatley E, Gay E, Cole J, Cottage A, Bolwell GP (2005). "Characterisation and expression of the pathway from UDP-glucose to UDP-xylose in differentiating tobacco tissue." Plant Mol Biol 57(2);285-301. PMID: 15821883

Boleda93: Boleda MD, Saubi N, Farres J, Pares X (1993). "Physiological substrates for rat alcohol dehydrogenase classes: aldehydes of lipid peroxidation, omega-hydroxyfatty acids, and retinoids." Arch Biochem Biophys 307(1);85-90. PMID: 8239669

Bosron87: Bosron WF, Li TK (1987). "Catalytic properties of human liver alcohol dehydrogenase isoenzymes." Enzyme 37(1-2);19-28. PMID: 3569190

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

Brown73: Brown AT, Patterson CE (1973). "Ethanol production and alcohol dehydrogenase activity in Streptococcus mutans." Arch Oral Biol 18(1);127-31. PMID: 4513107

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

Burnell87: Burnell JC, Carr LG, Dwulet FE, Edenberg HJ, Li TK, Bosron WF (1987). "The human beta 3 alcohol dehydrogenase subunit differs from beta 1 by a Cys for Arg-369 substitution which decreases NAD(H) binding." Biochem Biophys Res Commun 146(3);1127-33. PMID: 3619918

Carr89: Carr LG, Xu Y, Ho WH, Edenberg HJ (1989). "Nucleotide sequence of the ADH2(3) gene encoding the human alcohol dehydrogenase beta 3 subunit." Alcohol Clin Exp Res 13(4);594-6. PMID: 2679216

Chang97: Chang C, Yoshida A (1997). "Human fatty aldehyde dehydrogenase gene (ALDH10): organization and tissue-dependent expression." Genomics 40(1);80-5. PMID: 9070922

Chrostek03a: Chrostek L, Jelski W, Szmitkowski M, Puchalski Z (2003). "Gender-related differences in hepatic activity of alcohol dehydrogenase isoenzymes and aldehyde dehydrogenase in humans." J Clin Lab Anal 17(3);93-6. PMID: 12696080

Clark89: Clark DP (1989). "The fermentation pathways of Escherichia coli." FEMS Microbiol Rev 1989;5(3);223-34. PMID: 2698228

Cotton88: Cotton RW, Goldman D (1988). "Review of the molecular biology of the human alcohol dehydrogenase genes and gene products." Adv Alcohol Subst Abuse 7(3-4);171-82. PMID: 3066190

Danielsson94: Danielsson O, Shafqat J, Estonius M, Jornvall H (1994). "Alcohol dehydrogenase class III contrasted to class I. Characterization of the cyclostome enzyme, the existence of multiple forms as for the human enzyme, and distant cross-species hybridization." Eur J Biochem 225(3);1081-8. PMID: 7957198

Day91: Day CP, Bashir R, James OF, Bassendine MF, Crabb DW, Thomasson HR, Li TK, Edenberg HJ (1991). "Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related end-organ damage." Hepatology 14(5);798-801. PMID: 1937384

De96b: 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

Dickinson03: Dickinson JR, Salgado LE, Hewlins MJ (2003). "The catabolism of amino acids to long chain and complex alcohols in Saccharomyces cerevisiae." J Biol Chem 278(10);8028-34. PMID: 12499363

Duester86: Duester G, Smith M, Bilanchone V, Hatfield GW (1986). "Molecular analysis of the human class I alcohol dehydrogenase gene family and nucleotide sequence of the gene encoding the beta subunit." J Biol Chem 261(5);2027-33. PMID: 2935533

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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 Nov 24, 2014, BIOCYC14B.