Editing Alcohol dehydrogenase (section)

== Types ==

=== Human ===
In humans, ADH exists in multiple forms as a [[Dimerization (chemistry)|dimer]] and is encoded by at least seven genes. Among the five classes (I-V) of alcohol dehydrogenase, the [[hepatic]] forms that are used primarily in humans are class 1. Class 1 consists of α, β, and γ subunits that are encoded by the genes [[ADH1A]], [[ADH1B]], and [[ADH1C]].<ref name="pmid14718645">{{cite journal | vauthors = Sultatos LG, Pastino GM, Rosenfeld CA, Flynn EJ | title = Incorporation of the genetic control of alcohol dehydrogenase into a physiologically based pharmacokinetic model for ethanol in humans | journal = Toxicological Sciences | volume = 78 | issue = 1 | pages = 20–31 | date = March 2004 | pmid = 14718645 | doi = 10.1093/toxsci/kfh057 | doi-access =  }}</ref><ref>{{cite journal | vauthors = Edenberg HJ, McClintick JN | title = Alcohol Dehydrogenases, Aldehyde Dehydrogenases, and Alcohol Use Disorders: A Critical Review | journal = Alcoholism: Clinical and Experimental Research | volume = 42 | issue = 12 | pages = 2281–2297 | date = December 2018 | pmid = 30320893 | doi = 10.1111/acer.13904 | pmc = 6286250 }}</ref> The enzyme is present at high levels in the [[liver]] and the lining of the [[stomach]].<ref name="Farrés">{{cite journal | vauthors = Farrés J, Moreno A, Crosas B, Peralba JM, Allali-Hassani A, Hjelmqvist L, Jörnvall H, Parés X | display-authors = 6 | title = Alcohol dehydrogenase of class IV (sigma sigma-ADH) from human stomach. cDNA sequence and structure/function relationships | journal = European Journal of Biochemistry | volume = 224 | issue = 2 | pages = 549–57 | date = September 1994 | pmid = 7925371 | doi = 10.1111/j.1432-1033.1994.00549.x | doi-access =  }}</ref> It catalyzes the [[oxidation]] of [[ethanol]] to [[acetaldehyde]] (ethanal):

:CH<sub>3</sub>CH<sub>2</sub>OH + NAD<sup>+</sup> → CH<sub>3</sub>CHO + [[NADH]] + H<sup>+</sup>

This allows the consumption of [[alcoholic beverage]]s, but its evolutionary purpose is probably the breakdown of alcohols naturally contained in foods or produced by [[bacteria]] in the [[digestive tract]].<ref name="urlwww.medicinenet.com">{{cite web | url = http://www.medicinenet.com/alcohol_and_nutrition/article.htm | title = Alcohol and Nutrition | vauthors = Kovacs B, Stöppler MC | publisher = MedicineNet, Inc. | access-date = 2011-06-07 | archive-url = https://web.archive.org/web/20110623122224/http://www.medicinenet.com/alcohol_and_nutrition/article.htm | archive-date = 23 June 2011 | url-status = dead }}</ref>

Another evolutionary purpose is reversible metabolism of [[retinol]] ([[vitamin A]]), an alcohol, to [[retinaldehyde]], also known as retinal, which is then irreversibly converted into [[retinoic acid]], which regulates expression of hundreds of genes.<ref name="Duester">{{cite journal | vauthors = Duester G | title = Retinoic acid synthesis and signaling during early organogenesis | journal = Cell | volume = 134 | issue = 6 | pages = 921–31 | date = September 2008 | pmid = 18805086 | pmc = 2632951 | doi = 10.1016/j.cell.2008.09.002 }}</ref><ref>{{cite journal | vauthors = Hellgren M, Strömberg P, Gallego O, Martras S, Farrés J, Persson B, Parés X, Höög JO | title = Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism | journal = Cellular and Molecular Life Sciences | volume = 64 | issue = 4 | pages = 498–505 | date = February 2007 | pmid = 17279314 | doi = 10.1007/s00018-007-6449-8 | s2cid = 21612648 | pmc = 11138474 }}</ref><ref>{{cite book |vauthors=Blaner WS |title = Present Knowledge in Nutrition, Eleventh Edition |chapter = Vitamin A | veditors = Marriott BP, Birt DF, Stallings VA, Yates AA |publisher = Academic Press (Elsevier) |year=2020 |location = London, United Kingdom |pages = 73–92 |isbn=978-0-323-66162-1}}</ref>

{|
|-
|{{infobox protein
| Name = [[ADH1A|alcohol dehydrogenase 1A,<br />α polypeptide]]
| caption =
| image =
| width =
| HGNCid = 249
| Symbol = [[ADH1A]]
| AltSymbols = ADH1
| EntrezGene = 124
| OMIM = 103700
| RefSeq = NM_000667
| UniProt = P07327
| PDB =
| ECnumber = 1.1.1.1
| CAS_number=
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[ADH1B|alcohol dehydrogenase 1B,<br />β polypeptide]]
| caption =
| image =
| width =
| HGNCid = 250
| Symbol = [[ADH1B]]
| AltSymbols = ADH2
| EntrezGene = 125
| OMIM = 103720
| RefSeq = NM_000668
| UniProt = P00325
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[ADH1C|alcohol dehydrogenase 1C,<br />γ polypeptide]]
| caption =
| image =
| width =
| HGNCid = 251
| Symbol = [[ADH1C]]
| AltSymbols = ADH3
| EntrezGene = 126
| OMIM = 103730
| RefSeq = NM_000669
| UniProt = P00326
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData =
}}
|}

Alcohol dehydrogenase is also involved in the toxicity of other types of alcohol: For instance, it oxidizes [[methanol]] to produce [[formaldehyde]] and ultimately [[formic acid]].<ref>{{cite book | vauthors = Ashurst JV, Nappe TM | chapter = Methanol Toxicity |date=2020 | chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK482121/| title = StatPearls |place= Treasure Island (FL)|publisher=StatPearls Publishing|pmid=29489213|access-date=2020-11-06}}</ref> Humans have at least six slightly different alcohol dehydrogenases. Each is a [[protein dimer|dimer]] (i.e., consists of two [[polypeptide]]s), with each dimer containing two [[zinc]] [[ion]]s Zn<sup>2+</sup>. One of those ions is crucial for the operation of the enzyme: It is located at the catalytic site and holds the [[hydroxyl]] group of the alcohol in place. {{Citation needed|date=February 2022}}

Alcohol dehydrogenase activity varies between men and women, between young and old, and among populations from different areas of the world. For example, young women are unable to process alcohol at the same rate as young men because they do not express the alcohol dehydrogenase as highly, although the inverse is true among the middle-aged.<ref name="pmid12107043">{{cite journal | vauthors = Parlesak A, Billinger MH, Bode C, Bode JC | title = Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a caucasian population | journal = Alcohol and Alcoholism | volume = 37 | issue = 4 | pages = 388–93 | year = 2002 | pmid = 12107043 | doi = 10.1093/alcalc/37.4.388 | doi-access = free }}</ref> The level of activity may not be dependent only on level of expression but also on [[allele|allelic]] diversity among the population.

The human genes that encode class II, III, IV, and V alcohol dehydrogenases are [[ADH4]], [[ADH5]], [[ADH7]], and [[ADH6]], respectively.
<div style="overflow:auto;">
{|
|-
|{{infobox protein
| Name = [[ADH4|alcohol dehydrogenase 4<br />(class II), π polypeptide]]
| caption =
| image =
| width =
| HGNCid = 252
| Symbol = [[ADH4]]
| AltSymbols =
| EntrezGene = 127
| OMIM = 103740
| RefSeq = NM_000670
| UniProt = P08319
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 22
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[ADH5|alcohol dehydrogenase 5<br />(class III), χ polypeptide]]
| caption =
| image =
| width =
| HGNCid = 253
| Symbol = [[ADH5]]
| AltSymbols =
| EntrezGene = 128
| OMIM = 103710
| RefSeq = NM_000671
| UniProt = P11766
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[ADH6|alcohol dehydrogenase 6<br />(class V)]]
| caption =
| image =
| width =
| HGNCid = 255
| Symbol = [[ADH6]]
| AltSymbols =
| EntrezGene = 130
| OMIM = 103735
| RefSeq = NM_000672
| UniProt = P28332
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData =
}}
|{{infobox protein
| Name = [[ADH7|alcohol dehydrogenase 7<br />(class IV), μ or σ polypeptide]]
| caption =
| image =
| width =
| HGNCid = 256
| Symbol = [[ADH7]]
| AltSymbols =
| EntrezGene = 131
| OMIM = 600086
| RefSeq = NM_000673
| UniProt = P40394
| PDB =
| ECnumber = 1.1.1.1
| Chromosome = 4
| Arm = q
| Band = 23
| LocusSupplementaryData = -q24 }}
|}</div>

=== Yeast and bacteria ===
Unlike humans, yeast and bacteria (except [[lactic acid bacteria]], and ''[[Escherichia coli|E. coli]]'' in certain conditions) do not ferment glucose to lactate. Instead, they ferment it to ethanol and {{co2}}. The overall reaction can be seen below:

: Glucose + 2 ADP + 2 Pi → 2 ethanol + 2 CO<sub>2</sub> + 2 ATP + 2 H<sub>2</sub>O<ref name="isbn0-7167-4339-6">{{cite book | vauthors = Cox M, Nelson DR, Lehninger AL | title = Lehninger Principles of Biochemistry | publisher = W. H. Freeman | location = San Francisco | year = 2005 | page = [https://archive.org/details/lehningerprincip00lehn_0/page/180 180] | isbn = 978-0-7167-4339-2 | url = https://archive.org/details/lehningerprincip00lehn_0/page/180 | url-access = registration }}</ref>

[[Image:AlcoholDehydrogenase-1A4U.png|thumb|left | Alcohol Dehydrogenase]]
In [[yeast]]<ref>{{cite journal | vauthors = Leskovac V, Trivić S, Pericin D | title = The three zinc-containing alcohol dehydrogenases from baker's yeast, Saccharomyces cerevisiae | journal = FEMS Yeast Research | volume = 2 | issue = 4 | pages = 481–94 | date = December 2002 | pmid = 12702265 | doi = 10.1111/j.1567-1364.2002.tb00116.x | doi-access = free }}</ref> and many [[bacteria]], alcohol dehydrogenase plays an important part in fermentation: [[Pyruvate]] resulting from [[glycolysis]] is converted to acetaldehyde and [[carbon dioxide]], and the acetaldehyde is then reduced to ethanol by an alcohol dehydrogenase called ADH1. The purpose of this latter step is the regeneration of NAD<sup>+</sup>, so that the energy-generating glycolysis can continue. Humans exploit this process to produce alcoholic beverages, by letting yeast ferment various fruits or grains. Yeast can produce and consume their own alcohol.

The main alcohol dehydrogenase in yeast is larger than the human one, consisting of four rather than just two subunits. It also contains zinc at its catalytic site. Together with the zinc-containing alcohol dehydrogenases of animals and humans, these enzymes from yeasts and many bacteria form the family of "long-chain"-alcohol dehydrogenases.{{cn|date=June 2024}}

[[Brewer's yeast]] also has another alcohol dehydrogenase, [[ADH2]], which evolved out of a duplicate version of the chromosome containing the [https://www.yeastgenome.org/locus/adh1 ADH1] gene. [https://www.yeastgenome.org/locus/adh2 ADH2] is used by the yeast to convert ethanol back into acetaldehyde, and it is expressed only when sugar concentration is low. Having these two enzymes allows yeast to produce alcohol when sugar is plentiful (and this alcohol then kills off competing microbes), and then continue with the oxidation of the alcohol once the sugar, and competition, is gone.<ref name="urlFestive special: The brewers tale - life - 23 December 2006 - New Scientist">{{cite magazine | url = https://www.newscientist.com/channel/life/mg19225831.100-festive-special-the-brewers-tale.html | title = Festive special: The brewer's tale – life | vauthors = Coghlan A | date = 23 December 2006 | magazine = New Scientist | access-date = 2009-04-27| archive-url= https://web.archive.org/web/20080915051831/http://www.newscientist.com/channel/life/mg19225831.100-festive-special-the-brewers-tale.html| archive-date=15 September 2008| url-status= live}}</ref>

===Plants===
In plants, ADH catalyses the same reaction as in yeast and bacteria to ensure that there is a constant supply of NAD<sup>+</sup>. [[Maize]] has two versions of ADH – ADH1 and ADH2, ''[[Arabidopsis thaliana]]'' contains only one ADH gene. The structure of ''Arabidopsis'' ADH is 47%-conserved, relative to ADH from horse liver.  Structurally and functionally important residues, such as the seven residues that provide ligands for the catalytic and noncatalytic zinc atoms, however, are conserved, suggesting that the enzymes have a similar structure.<ref>{{cite journal | vauthors = Chang C, Meyerowitz EM | title = Molecular cloning and DNA sequence of the Arabidopsis thaliana alcohol dehydrogenase gene | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 83 | issue = 5 | pages = 1408–12 | date = March 1986 | pmid = 2937058 | pmc = 323085 | doi = 10.1073/pnas.83.5.1408 | bibcode = 1986PNAS...83.1408C | doi-access = free }}</ref> ADH is constitutively expressed at low levels in the roots of young plants grown on agar.  If the roots lack oxygen, the expression of ''ADH'' increases significantly.<ref>{{cite journal | vauthors = Chung HJ, Ferl RJ | title = Arabidopsis alcohol dehydrogenase expression in both shoots and roots is conditioned by root growth environment | journal = Plant Physiology | volume = 121 | issue = 2 | pages = 429–36 | date = October 1999 | pmid = 10517834 | pmc = 59405 | doi = 10.1104/pp.121.2.429 }}</ref> Its expression is also increased in response to dehydration, to low temperatures, and to [[abscisic acid]], and it plays an important role in fruit ripening, seedlings development, and pollen development.<ref name=Thompson>{{cite journal | vauthors = Thompson CE, Fernandes CL, de Souza ON, de Freitas LB, Salzano FM | title = Evaluation of the impact of functional diversification on Poaceae, Brassicaceae, Fabaceae, and Pinaceae alcohol dehydrogenase enzymes | journal = Journal of Molecular Modeling | volume = 16 | issue = 5 | pages = 919–28 | date = May 2010 | pmid = 19834749 | doi = 10.1007/s00894-009-0576-0 | s2cid = 24730389 }}</ref> Differences in the sequences of ''ADH'' in different species have been used to create [[phylogeny|phylogenies]] showing how closely related different species of plants are.<ref>{{cite journal | vauthors = Järvinen P, Palmé A, Orlando Morales L, Lännenpää M, Keinänen M, Sopanen T, Lascoux M | title = Phylogenetic relationships of Betula species (Betulaceae) based on nuclear ADH and chloroplast matK sequences | journal = American Journal of Botany | volume = 91 | issue = 11 | pages = 1834–45 | date = November 2004 | pmid = 21652331 | doi = 10.3732/ajb.91.11.1834 }}</ref> It is an ideal gene to use due to its convenient size (2–3 kb in length with a ≈1000 nucleotide coding sequence) and low copy number.<ref name=Thompson/>

=== Iron-containing ===
{{Infobox protein family
| Symbol = Fe-ADH
| Name = Iron-containing alcohol dehydrogenase
| image = PDB 1jqa EBI.jpg
| width =
| caption = bacillus stearothermophilus glycerol dehydrogenase complex with glycerol
| Pfam = PF00465
| Pfam_clan = CL0224
| InterPro = IPR001670
| SMART =
| PROSITE = PDOC00059
| MEROPS =
| SCOP = 1jqa
| TCDB =
| =
| OPM protein =
| CAZy =
| CDD =
}}
A third family of alcohol dehydrogenases, unrelated to the above two, are [[iron]]-containing ones. They occur in bacteria and fungi. In comparison to enzymes the above families, these enzymes are oxygen-sensitive.{{Citation needed|date=August 2011}}
Members of the iron-containing alcohol dehydrogenase family include:
* ''[[Saccharomyces cerevisiae]]'' alcohol dehydrogenase 4 (gene ADH4)<ref name="pmid2823079">{{cite journal | vauthors = Williamson VM, Paquin CE | title = Homology of Saccharomyces cerevisiae ADH4 to an iron-activated alcohol dehydrogenase from Zymomonas mobilis | journal = Molecular & General Genetics | volume = 209 | issue = 2 | pages = 374–81 | date = September 1987 | pmid = 2823079 | doi = 10.1007/bf00329668 | s2cid = 22397371 }}</ref>
* ''[[Zymomonas mobilis]]'' alcohol dehydrogenase 2 (gene adhB)<ref name="pmid3584063">{{cite journal | vauthors = Conway T, Sewell GW, Osman YA, Ingram LO | title = Cloning and sequencing of the alcohol dehydrogenase II gene from Zymomonas mobilis | journal = Journal of Bacteriology | volume = 169 | issue = 6 | pages = 2591–7 | date = June 1987 | pmid = 3584063 | pmc = 212129 | doi =  10.1128/jb.169.6.2591-2597.1987}}</ref>
* ''[[Escherichia coli]]'' propanediol oxidoreductase {{EC number|1.1.1.77}} (gene fucO),<ref name="pmid2661535">{{cite journal | vauthors = Conway T, Ingram LO | title = Similarity of Escherichia coli propanediol oxidoreductase (fucO product) and an unusual alcohol dehydrogenase from Zymomonas mobilis and Saccharomyces cerevisiae | journal = Journal of Bacteriology | volume = 171 | issue = 7 | pages = 3754–9 | date = July 1989 | pmid = 2661535 | pmc = 210121 | doi =  10.1128/jb.171.7.3754-3759.1989}}</ref> an [[enzyme]] involved in the [[metabolism]] of [[fucose]] and which also seems to contain [[ferrous]] ion(s).
* ''[[Clostridium acetobutylicum]]'' [[NADPH]]- and [[NADH]]-dependent butanol dehydrogenases {{EC number|1.1.1.-}} (genes adh1, bdhA and bdhB),<ref name="pmid1385386">{{cite journal | vauthors = Walter KA, Bennett GN, Papoutsakis ET | title = Molecular characterization of two Clostridium acetobutylicum ATCC 824 butanol dehydrogenase isozyme genes | journal = Journal of Bacteriology | volume = 174 | issue = 22 | pages = 7149–58 | date = November 1992 | pmid = 1385386 | pmc = 207405 | doi =  10.1128/jb.174.22.7149-7158.1992}}</ref> enzymes that have activity using [[butanol]] and [[ethanol]] as [[substrate (biochemistry)|substrates]].
* ''E. coli'' adhE,<ref name="pmid2015910">{{cite journal | vauthors = Kessler D, Leibrecht I, Knappe J | title = Pyruvate-formate-lyase-deactivase and acetyl-CoA reductase activities of Escherichia coli reside on a polymeric protein particle encoded by adhE | journal = FEBS Letters | volume = 281 | issue = 1–2 | pages = 59–63 | date = April 1991 | pmid = 2015910 | doi = 10.1016/0014-5793(91)80358-A | s2cid = 22541869 | doi-access =  | bibcode = 1991FEBSL.281...59K }}</ref> an iron-dependent enzyme that harbours three different activities: alcohol dehydrogenase, [[acetaldehyde dehydrogenase]] (acetylating) {{EC number|1.2.1.10}} and pyruvate-formate-lyase deactivase.
* [[Bacteria]]l [[glycerol dehydrogenase]] {{EC number|1.1.1.6}} (gene gldA or dhaD).<ref name="pmid8132480">{{cite journal | vauthors = Truniger V, Boos W | title = Mapping and cloning of gldA, the structural gene of the Escherichia coli glycerol dehydrogenase | journal = Journal of Bacteriology | volume = 176 | issue = 6 | pages = 1796–800 | date = March 1994 | pmid = 8132480 | pmc = 205274 | doi =  10.1128/jb.176.6.1796-1800.1994}}</ref>
* ''[[Clostridium kluyveri]]'' NAD-dependent [[4-hydroxybutyrate dehydrogenase]] (4hbd) {{EC number|1.1.1.61}}
* ''[[Citrobacter freundii]]'' and ''[[Klebsiella pneumoniae]]'' [[1,3-propanediol dehydrogenase]] {{EC number|1.1.1.202}} (gene dhaT)
* ''Bacillus methanolicus'' NAD-dependent [[methanol dehydrogenase]] {{EC number|1.1.1.244}}<ref name="pmid1644761">{{cite journal | vauthors = de Vries GE, Arfman N, Terpstra P, Dijkhuizen L | title = Cloning, expression, and sequence analysis of the Bacillus methanolicus C1 methanol dehydrogenase gene | journal = Journal of Bacteriology | volume = 174 | issue = 16 | pages = 5346–53 | date = August 1992 | pmid = 1644761 | pmc = 206372 | doi =  10.1128/jb.174.16.5346-5353.1992}}</ref>
* ''E. coli'' and ''[[Salmonella typhimurium]]'' [[ethanolamine]] utilization [[protein]] eutG.
* ''E. coli'' hypothetical protein yiaY.

=== Other types ===
A further class of alcohol dehydrogenases belongs to quinoenzymes and requires quinoid cofactors (e.g., pyrroloquinoline quinone, PQQ) as enzyme-bound electron acceptors. A typical example for this type of enzyme is methanol dehydrogenase of methylotrophic bacteria.