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
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 and alcohol dehydrogenase pathways [Chrostek03a].
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].
Chrostek03a: 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
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
Auchter09: Auchter M, Arndt A, Eikmanns BJ (2009). "Dual transcriptional control of the acetaldehyde dehydrogenase gene ald of Corynebacterium glutamicum by RamA and RamB." J Biotechnol 140(1-2);84-91. PMID: 19041911
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
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
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
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
Chrostek03: 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
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
De96: 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
Showing only 20 references. To show more, press the button "Show all references".
©2014 SRI International, 333 Ravenswood Avenue, Menlo Park, CA 94025-3493