ADH4 explained

Alcohol dehydrogenase 4 is an enzyme that in humans is encoded by the ADH4 gene.^[1]

This gene encodes class II alcohol dehydrogenase 4 pi subunit, which is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class II alcohol dehydrogenase is a homodimer composed of 2 pi subunits. It exhibits a high activity for oxidation of long-chain aliphatic alcohols and aromatic alcohols and is less sensitive to pyrazole. This gene is localized to chromosome 4 in the cluster of alcohol dehydrogenase genes.

There is evidence that ancestors of modern humans developed the ADH4 producing gene some 10 million years ago. This probably helped them to take advantage of rotting fruit as they shifted to a terrestrial lifestyle.^[2]

Further reading

• Book: Jörnvall H . The alcohol dehydrogenase system . Toward a Molecular Basis of Alcohol Use and Abuse . Exs . 71 . 221–9 . 1994 . 8032153 . 10.1007/978-3-0348-7330-7_22. 978-3-0348-7332-1 .
• Edman K, Maret W . Alcohol dehydrogenase genes: restriction fragment length polymorphisms for ADH4 (pi-ADH) and ADH5 (chi-ADH) and construction of haplotypes among different ADH classes. . Hum. Genet. . 90 . 4 . 395–401 . 1993 . 1362387 . 10.1007/bf00220466. 30770835 .
• von Bahr-Lindström H, Jörnvall H, Höög JO . Cloning and characterization of the human ADH4 gene. . Gene . 103 . 2 . 269–74 . 1991 . 1889753 . 10.1016/0378-1119(91)90285-J .
• Höög JO, von Bahr-Lindström H, Hedén LO . 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 . 1987 . 3036213 . 10.1021/bi00381a021 . etal.
• Mårdh G, Dingley AL, Auld DS, Vallee BL . 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 . 1987 . 3466164 . 10.1073/pnas.83.23.8908 . 387042 . free .
• Li M, Edenberg HJ . Function of cis-acting elements in human alcohol dehydrogenase 4 (ADH4) promoter and role of C/EBP proteins in gene expression. . DNA Cell Biol. . 17 . 4 . 387–97 . 1998 . 9570155 . 10.1089/dna.1998.17.387 .
• Tryggvason K, Romert A, Eriksson U . Biosynthesis of 9-cis-retinoic acid in vivo. The roles of different retinol dehydrogenases and a structure-activity analysis of microsomal retinol dehydrogenases. . J. Biol. Chem. . 276 . 22 . 19253–8 . 2001 . 11279029 . 10.1074/jbc.M100215200 . free .
• Xu XR, Huang J, Xu ZG . Insight into hepatocellular carcinogenesis at transcriptome level by comparing gene expression profiles of hepatocellular carcinoma with those of corresponding noncancerous liver. . Proc. Natl. Acad. Sci. U.S.A. . 98 . 26 . 15089–94 . 2002 . 11752456 . 10.1073/pnas.241522398 . 64988 . 2001PNAS...9815089X . etal. free .
• Iida A, Saito S, Sekine A . Thirteen single-nucleotide polymorphisms (SNPs) in the alcohol dehydrogenase 4 (ADH4) gene locus. . J. Hum. Genet. . 47 . 2 . 74–6 . 2002 . 11916005 . 10.1007/s100380200003 . etal. free .
• Strömberg P, Svensson S, Hedberg JJ . Identification and characterisation of two allelic forms of human alcohol dehydrogenase 2. . Cell. Mol. Life Sci. . 59 . 3 . 552–9 . 2002 . 11964133 . 10.1007/s00018-002-8447-1 . 21451213 . etal.
• Chou CF, Lai CL, Chang YC . Kinetic mechanism of human class IV alcohol dehydrogenase functioning as retinol dehydrogenase. . J. Biol. Chem. . 277 . 28 . 25209–16 . 2002 . 11997393 . 10.1074/jbc.M201947200 . etal. free .
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• Galter D, Carmine A, Buervenich S . Distribution of class I, III and IV alcohol dehydrogenase mRNAs in the adult rat, mouse and human brain. . Eur. J. Biochem. . 270 . 6 . 1316–26 . 2003 . 12631290 . 10.1046/j.1432-1033.2003.03502.x . etal. free .
• Neumark YD, Friedlander Y, Durst R . Alcohol dehydrogenase polymorphisms influence alcohol-elimination rates in a male Jewish population. . Alcohol. Clin. Exp. Res. . 28 . 1 . 10–4 . 2004 . 14745297 . 10.1097/01.ALC.0000108667.79219.4D . etal.
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Luo X, Kranzler HR, Zuo L . ADH4 gene variation is associated with alcohol and drug dependence: results from family controlled and population-structured association studies. . Pharmacogenet. Genomics . 15 . 11 . 755–68 . 2006 . 16220108 . 10.1097/01.fpc.0000180141.77036.dc . 38408639 . etal.
• Luo X, Kranzler HR, Zuo L . ADH4 gene variation is associated with alcohol dependence and drug dependence in European Americans: results from HWD tests and case-control association studies. . Neuropsychopharmacology . 31 . 5 . 1085–95 . 2006 . 16237392 . 10.1038/sj.npp.1300925 . etal. free .
• Luo X, Kranzler HR, Zuo L . Personality traits of agreeableness and extraversion are associated with ADH4 variation. . Biol. Psychiatry . 61 . 5 . 599–608 . 2007 . 17069770 . 10.1016/j.biopsych.2006.05.017 . 1853245 . etal.
• Carrigana MA, Uryasev O . Hominids adapted to metabolize ethanol long before human-directed fermentation. . Proc. Natl. Acad. Sci. USA . 112 . 2 . 599–608 . 2014 . 25453080. 10.1073/pnas.1404167111. etal . 4299227. free .

Notes and References

1. Web site: Entrez Gene: ADH4 alcohol dehydrogenase 4 (class II), pi polypeptide.
2. Choi . Charles Q. . Origins of Human Alcohol Consumption Revealed . Scientific American . Dec 2, 2014 . 18 May 2023.