|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 [Harada01a, Danielsson94]. The family of alcohol dehydrogenases consists of up to 20 distinct isoenzymes [Salway04]. 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, Chrostek03]. 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 [Chrostek03]. Furthermore, the relative activity of ADHs within a given tissue may vary by gender [Chrostek03]. 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 [Chrostek03a].
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].
|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
|Cellular Component:||GO:0005829 - cytosol [Mardh86]|
Enzymatic reaction of: 3,4-dihydroxyphenylglycolaldehyde reductase (alcohol dehydrogenase 4)
The reaction direction shown, that is, A + B ↔ C + D versus C + D ↔ A + B, is in accordance with the Enzyme Commission system.
The reaction is favored in the opposite direction.
In Pathways: noradrenaline and adrenaline degradation
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
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). "Alcohol dehydrogenase (ADH) isoenzymes and aldehyde dehydrogenase (ALDH) activity in the human pancreas." Dig Dis Sci 48(7);1230-3. PMID: 12870777
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
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
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
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
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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