Editing Alcohol dehydrogenase (section)

== Evolution ==
Genetic evidence from comparisons of multiple organisms showed that a [[glutathione]]-dependent [[formaldehyde dehydrogenase]], identical to a [[ADH5|class III alcohol dehydrogenase]] (ADH-3/ADH5), is presumed to be the ancestral enzyme for the entire ADH family.<ref name="pmid1731906">{{cite journal | vauthors = Gutheil WG, Holmquist B, Vallee BL | title = Purification, characterization, and partial sequence of the glutathione-dependent formaldehyde dehydrogenase from Escherichia coli: a class III alcohol dehydrogenase | journal = Biochemistry | volume = 31 | issue = 2 | pages = 475–81 | date = January 1992 | pmid = 1731906 | doi = 10.1021/bi00117a025 }}</ref><ref name="pmid1409630">{{cite journal | vauthors = Danielsson O, Jörnvall H | title = "Enzymogenesis": classical liver alcohol dehydrogenase origin from the glutathione-dependent formaldehyde dehydrogenase line | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 19 | pages = 9247–51 | date = October 1992 | pmid = 1409630 | pmc = 50103 | doi = 10.1073/pnas.89.19.9247 | bibcode = 1992PNAS...89.9247D | doi-access = free }}</ref><ref name="pmid19011751">{{cite journal | vauthors = Persson B, Hedlund J, Jörnvall H | title = Medium- and short-chain dehydrogenase/reductase gene and protein families : the MDR superfamily | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 24 | pages = 3879–94 | date = December 2008 | pmid = 19011751 | pmc = 2792335 | doi = 10.1007/s00018-008-8587-z }}</ref> Early on in evolution, an effective method for eliminating both endogenous and exogenous formaldehyde was important and this capacity has conserved the ancestral ADH-3 through time. [[Gene duplication]] of ADH-3, followed by series of mutations, led to the evolution of other ADHs.<ref name="pmid1409630"/><ref name="pmid19011751"/>

The ability to produce [[ethanol]] from sugar (which is the basis of how alcoholic beverages are made) is believed to have initially evolved in [[yeast]]. Though this feature is not adaptive from an energy point of view, by making alcohol in such high concentrations so that they would be toxic to other organisms, yeast cells could effectively eliminate their competition. Since rotting fruit can contain more than 4% of ethanol, animals eating the fruit needed a system to metabolize exogenous ethanol. This was thought to explain the conservation of ethanol active ADH in species other than yeast, though ADH-3 is now known to also have a major role in [[Signal transduction#Nitric oxide|nitric oxide signaling]].<ref name="pmid19011746">{{cite journal | vauthors = Staab CA, Hellgren M, Höög JO | title = Medium- and short-chain dehydrogenase/reductase gene and protein families : Dual functions of alcohol dehydrogenase 3: implications with focus on formaldehyde dehydrogenase and S-nitrosoglutathione reductase activities | journal = Cellular and Molecular Life Sciences | volume = 65 | issue = 24 | pages = 3950–60 | date = December 2008 | pmid = 19011746 | doi = 10.1007/s00018-008-8592-2 | s2cid = 8574022 | pmc = 11131861 }}</ref><ref name="pmid16763671">{{cite journal | vauthors = Godoy L, Gonzàlez-Duarte R, Albalat R | title = S-Nitrosogluthathione reductase activity of amphioxus ADH3: insights into the nitric oxide metabolism | journal = International Journal of Biological Sciences | volume = 2 | issue = 3 | pages = 117–24 | year = 2006 | pmid = 16763671 | pmc = 1458435 | doi = 10.7150/ijbs.2.117 }}</ref>

In humans, sequencing of the [[ADH1B]] gene (responsible for production of an alcohol dehydrogenase [[polypeptide]]) shows several functional variants. In one, there is a [[single nucleotide polymorphism|SNP]] (single nucleotide polymorphism) that leads to either a Histidine or an Arginine residue at position 47 in the mature polypeptide. In the Histidine variant, the enzyme is much more effective at the aforementioned conversion.<ref name="whitfield">{{cite journal|vauthors=Whitfield, John B |title=ADH and ALDH genotypes in relation to alcohol metabolic rate and sensitivity |journal=Alcohol and Alcoholism |volume=2 |pages=59–65 |url=http://152.98.160.29/contents/p/staff/JW058.pdf |archive-url=https://ghostarchive.org/archive/20221009/http://152.98.160.29/contents/p/staff/JW058.pdf |archive-date=2022-10-09 |url-status=live |pmid=8974317 |year=1994 }}{{dead link|date=June 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The enzyme responsible for the conversion of acetaldehyde to acetate, however, remains unaffected, which leads to differential rates of substrate catalysis and causes a buildup of toxic acetaldehyde, causing cell damage.<ref name = whitfield /> This provides some protection against excessive alcohol consumption and alcohol dependence (alcoholism).<ref name=":0">{{cite journal | vauthors = Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, Yin SJ | title = Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men | journal = American Journal of Human Genetics | volume = 48 | issue = 4 | pages = 677–81 | date = April 1991 | pmid = 2014795 | pmc = 1682953 }}</ref><ref name=":1">{{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 = October 2018 | pmid = 30320893 | pmc = 6286250 | doi = 10.1111/acer.13904 }}</ref><ref name=":2">{{cite journal | vauthors = Hurley TD, Edenberg HJ | title = Genes encoding enzymes involved in ethanol metabolism | journal = Alcohol Research | volume = 34 | issue = 3 | pages = 339–44 | date = 2012 | pmid = 23134050 | pmc = 3756590 }}</ref><ref name=":3">{{cite journal | vauthors = Walters RK, Polimanti R, Johnson EC, McClintick JN, Adams MJ, Adkins AE, etal | title = Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders | journal = Nature Neuroscience | volume = 21 | issue = 12 | pages = 1656–1669 | date = December 2018 | pmid = 30482948 | pmc = 6430207 | doi = 10.1038/s41593-018-0275-1 }}</ref> Various haplotypes arising from this mutation are more concentrated in regions near Eastern China, a region also known for its low alcohol tolerance and dependence.

A study was conducted in order to find a correlation between allelic distribution and alcoholism, and the results suggest that the allelic distribution arose along with rice cultivation in the region between 12,000 and 6,000 years ago.<ref name = rice >{{cite journal | vauthors = Peng Y, Shi H, Qi XB, Xiao CJ, Zhong H, Ma RL, Su B | title = The ADH1B Arg47His polymorphism in east Asian populations and expansion of rice domestication in history | journal = BMC Evolutionary Biology | volume = 10 | pages = 15 | date = January 2010 | issue = 1 | pmid = 20089146 | pmc = 2823730 | doi = 10.1186/1471-2148-10-15 | bibcode = 2010BMCEE..10...15P | doi-access = free }}</ref> In regions where rice was cultivated, rice was also fermented into ethanol.<ref name = rice /> This led to speculation that increased alcohol availability led to alcoholism and abuse, resulting in lower reproductive fitness.<ref name = rice /> Those with the variant allele have little tolerance for alcohol, thus lowering chance of dependence and abuse.<ref name = whitfield /><ref name = rice /> The hypothesis posits that those individuals with the Histidine variant enzyme were sensitive enough to the effects of alcohol that differential reproductive success arose and the corresponding alleles were passed through the generations. Classical [[Darwinian evolution]] would act to select against the detrimental form of the enzyme (Arg variant) because of the lowered reproductive success of individuals carrying the allele. The result would be a higher frequency of the allele responsible for the His-variant enzyme in regions that had been under selective pressure the longest. The distribution and frequency of the His variant follows the spread of rice cultivation to inland regions of Asia, with higher frequencies of the His variant in regions that have cultivated rice the longest.<ref name="whitfield" /> The geographic distribution of the alleles seems to therefore be a result of natural selection against individuals with lower reproductive success, namely, those who carried the Arg variant allele and were more susceptible to alcoholism.<ref>{{cite journal| vauthors = Eng MY |title=Alcohol Research and Health|journal=Alcohol Health & Research World |date=2007-01-01|publisher=U.S. Government Printing Office|issn=1535-7414}}</ref> However, the persistence of the Arg variant in other populations argues that the effect could not be strong.{{cn|date=February 2024}}