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MetaCyc Enzyme: alcohol dehydrogenase 4

Gene: ADH4 Accession Number: G-11576 (MetaCyc)

Synonyms: alcohol dehydrogenase class II pi chain

Species: Homo sapiens

Subunit composition of alcohol dehydrogenase 4 = [ADH4]2
         alcohol dehydrogenase 4 subunit = ADH4

Multiple forms and gene loci for human alcohol dehydrogenase (ADH) have been identified and characterized [Harada01, Danielsson94]. The family of alcohol dehydrogenases consists of up to 20 distinct isoenzymes [Salway04b]. Members of this family metabolize a wide variety of substrates including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products [Boleda93]. Alcohol dehydrogenase 2 (alcohol:NAD+ oxidoreductase) exhibits high activity for ethanol oxidation and plays a major role in oxidative ethanol degradation [Kaiser93].

Four major classes of ADHs have been identified in humans and differentiated on the basis of physical properties, structure, and tissue distribution [Cotton88, Rosell03]. Class I ADHs are widespread but show significant activity variability across different tissues. Conversely, class II ADHs have limited tissue distribution whilst class III ADHs are abundant but show little variability of activity [Hoog94]. Under normal physiological conditions, class I alcohol dehydrogenases (alcohol dehydrogenase 2) mediate the majority of hepatic ethanol oxidation [Kaiser93].

The distribution of isoenzymes varies by tissue such that the relative activities of the different ADH classes vary from tissue to tissue [Boleda93, Wierzchowski92, Chrostek03a]. For example, in pancreas class III isoenzyme exhibited the highest activity of all ADH isoenzymes tested and it was about 7 times higher than the activity of class I but the activities of II and IV were low [Chrostek03a]. Furthermore, the relative activity of ADHs within a given tissue may vary by gender [Chrostek03a]. For example, ADH isoenzyme activities have been measured in the livers of male and female patients and total ADH and class I and II activities were found to be significantly higher in males than in females [Chrostek03].

Alcohol dehydrogenases function as dimers which arise from association of eight distinct subunits (alpha, beta 1, beta 2, beta 3, gamma 1, gamma 2, pi and chi) into active dimeric molecules. Subunits hybridize within but not between classes [Bosron87]. There are three types of subunit in class I - alpha, beta and gamma [Yasunami90]. All known isoenzymes (homodimeric and heterodimeric) have been isolated and purified to homogeneity [Bosron87]. Kinetic studies of the isoenzymes demonstrate marked differences in substrate and inhibitor specificities and catalytic activities [Burnell87, Boleda93]. For example, the Km values for NAD+ and ethanol vary up to 1,000-fold across isoenzymes.

Polymorphic variants, including a common functional variant of class I ADHs have also been identified [Cotton88, Carr89]. Variants show distinct kinetic properties [Hurley90]. A common variant results from a single nucleotide polymorphism [Matsuo89]. The presence of variants may influence the risk and severity of alcoholism [Hasin02].

Gene Citations: [vonBahrLindstro91 , Hoog87]

Locations: cytosol

Map Position: [100,044,832 <- 100,065,449]

Molecular Weight of Polypeptide: 40.222 kD (from nucleotide sequence)

Unification Links: ArrayExpress:P08319, Entrez-gene:127, PhosphoSite:P08319, PhylomeDB:P08319, Pride:P08319, Protein Model Portal:P08319, SMR:P08319, String:9606.ENSP00000265512, UniProt:P08319

Relationship Links: InterPro:IN-FAMILY:IPR002085, InterPro:IN-FAMILY:IPR002328, InterPro:IN-FAMILY:IPR011032, InterPro:IN-FAMILY:IPR013149, InterPro:IN-FAMILY:IPR013154, InterPro:IN-FAMILY:IPR016040, InterPro:IN-FAMILY:IPR028632, Panther:IN-FAMILY:PTHR11695, Panther:IN-FAMILY:PTHR11695:SF308, PDB:Structure:3COS, Pfam:IN-FAMILY:PF00107, Pfam:IN-FAMILY:PF08240, Prosite:IN-FAMILY:PS00059

Gene-Reaction Schematic

Gene-Reaction Schematic

GO Terms:
Cellular Component:
GO:0005829 - cytosol [Mardh86]

Created 02-Oct-2009 by Fulcher CA, SRI International

Enzymatic reaction of: 3,4-dihydroxyphenylglycolaldehyde reductase (alcohol dehydrogenase 4)

Inferred from experiment

3,4-dihydroxyphenylglycol + NAD+ ← 3,4-dihydroxyphenylglycolaldehyde + NADH + H+

The direction shown, i.e. which substrates are on the left and right sides, is in accordance with the Enzyme Commission system.

The reaction is favored in the opposite direction.

In Pathways: noradrenaline and adrenaline degradation

Experiments suggested that human alcohol dehydrogenase 4 functions in the reduction of 3,4-dihydroxyphenylglycolaldehyde during the metabolismn of noradrenaline [Mardh86].

Kinetic Parameters:
Substrate Km (μM) Citations
3,4-dihydroxyphenylglycolaldehyde 55.0 [Mardh86]


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

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

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

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

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

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

Hasin02: Hasin D, Aharonovich E, Liu X, Mamman Z, Matseoane K, Carr And LG, Li TK (2002). "Alcohol dependence symptoms and alcohol dehydrogenase 2 polymorphism: Israeli Ashkenazis, Sephardics, and recent Russian immigrants." Alcohol Clin Exp Res 26(9);1315-21. PMID: 12351924

Hoog87: Hoog JO, von Bahr-Lindstrom H, Heden LO, Holmquist B, Larsson K, Hempel J, Vallee BL, Jornvall H (1987). "Structure of the class II enzyme of human liver alcohol dehydrogenase: combined cDNA and protein sequence determination of the pi subunit." Biochemistry 26(7);1926-32. PMID: 3036213

Hoog94: Hoog JO, Estonius M, Danielsson O (1994). "Site-directed mutagenesis and enzyme properties of mammalian alcohol dehydrogenases correlated with their tissue distribution." EXS 71;301-9. PMID: 8032161

Hurley90: Hurley TD, Edenberg HJ, Bosron WF (1990). "Expression and kinetic characterization of variants of human beta 1 beta 1 alcohol dehydrogenase containing substitutions at amino acid 47." J Biol Chem 265(27);16366-72. PMID: 2398055

Kaiser93: Kaiser R, Fernandez MR, Pares X, Jornvall H (1993). "Origin of the human alcohol dehydrogenase system: implications from the structure and properties of the octopus protein." Proc Natl Acad Sci U S A 90(23);11222-6. PMID: 8248232

Mardh86: Mardh G, Dingley AL, Auld DS, Vallee BL (1986). "Human class II (pi) alcohol dehydrogenase has a redox-specific function in norepinephrine metabolism." Proc Natl Acad Sci U S A 83(23);8908-12. PMID: 3466164

Matsuo89: Matsuo Y, Yokoyama R, Yokoyama S (1989). "The genes for human alcohol dehydrogenases beta 1 and beta 2 differ by only one nucleotide." Eur J Biochem 183(2);317-20. PMID: 2547609

Rosell03: Rosell A, Valencia E, Pares X, Fita I, Farres J, Ochoa WF (2003). "Crystal structure of the vertebrate NADP(H)-dependent alcohol dehydrogenase (ADH8)." J Mol Biol 330(1);75-85. PMID: 12818203

Salway04b: Salway, J.G., Granner, D.K. (2004). "Metabolism at a Glance, Second Edition." Blackwell Publishing, ISBN:1405107162.

vonBahrLindstro91: von Bahr-Lindstrom H, Jornvall H, Hoog JO (1991). "Cloning and characterization of the human ADH4 gene." Gene 103(2);269-74. PMID: 1889753

Wierzchowski92: Wierzchowski J, Holmquist B, Vallee BL (1992). "Determination of human serum alcohol dehydrogenase using isozyme-specific fluorescent substrates." Anal Chem 64(2);181-6. PMID: 1616124

Yasunami90: Yasunami M, Kikuchi I, Sarapata D, Yoshida A (1990). "The human class I alcohol dehydrogenase gene cluster: three genes are tandemly organized in an 80-kb-long segment of the genome." Genomics 7(2);152-8. PMID: 2347582

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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