Alcohol dehydrogenase: Difference between revisions
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{{enzyme | {{enzyme | ||
| Name = | | Name = Alcohol dehydrogenase | ||
| EC_number = 1.1.1.1 | | EC_number = 1.1.1.1 | ||
| IUBMB_EC_number = 1/1/1/1 | | IUBMB_EC_number = 1/1/1/1 | ||
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| image = Protein ADH5 PDB 1m6h.png | | image = Protein ADH5 PDB 1m6h.png | ||
| width = | | width = | ||
| caption = [[Protein crystallography|Crystallographic]] structure of the<br>homodimer of human [[ADH5]].<ref name="pmid12196016">{{PDB|1m6h}}; {{cite journal | vauthors = Sanghani PC, Robinson H, Bosron WF, Hurley TD | title = Human glutathione-dependent formaldehyde dehydrogenase. Structures of apo, binary, and inhibitory ternary complexes | journal = Biochemistry | volume = 41 | issue = 35 | pages = 10778–86 |date=September 2002 | pmid = 12196016 | doi = 10.1021/bi0257639 | | caption = [[Protein crystallography|Crystallographic]] structure of the<br>homodimer of human [[ADH5]].<ref name="pmid12196016">{{PDB|1m6h}}; {{cite journal | vauthors = Sanghani PC, Robinson H, Bosron WF, Hurley TD | title = Human glutathione-dependent formaldehyde dehydrogenase. Structures of apo, binary, and inhibitory ternary complexes | journal = Biochemistry | volume = 41 | issue = 35 | pages = 10778–86 | date = September 2002 | pmid = 12196016 | doi = 10.1021/bi0257639 }}</ref> | ||
}} | }} | ||
'''Alcohol dehydrogenases''' ('''ADH''') ({{EC number|1.1.1.1}}) are a group of [[dehydrogenase]] [[enzyme]]s that occur in many organisms and facilitate the interconversion between [[alcohol]]s and [[aldehyde]]s or [[ketone]]s with the reduction of [[nicotinamide adenine dinucleotide]] (NAD<sup>+</sup> to NADH | '''Alcohol dehydrogenases''' ('''ADH''') ({{EC number|1.1.1.1}}) are a group of [[dehydrogenase]] [[enzyme]]s that occur in many organisms and facilitate the interconversion between [[alcohol]]s and [[aldehyde]]s or [[ketone]]s with the reduction of [[nicotinamide adenine dinucleotide]] (NAD<sup>+</sup>) to NADH. In [[human]]s and many other [[animal]]s, they serve to break down alcohols that otherwise are toxic, and they also participate in generation of useful aldehyde, ketone, or alcohol groups during biosynthesis of various [[metabolites]]. In [[yeast]], plants, and many [[bacteria]], some alcohol dehydrogenases [[catalysis|catalyze]] the opposite reaction as part of [[fermentation (food)|fermentation]] to ensure a constant supply of NAD<sup>+</sup>. | ||
== Evolution == | == 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 = | 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 }}</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 other | 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 }}</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 | 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 |url=http://152.98.160.29/contents/p/staff/JW058.pdf }}{{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>{{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>{{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 | date = October 2018 | pmid = 30320893 | doi = 10.1111/acer.13904 }}</ref><ref>{{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>. 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 = 2010 | pmid = 20089146 | doi = 10.1186/1471-2148-10-15 | url = http://www.biomedcentral.com/1471-2148/10/15 | 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 | pmid = 20089146 | pmc = 2823730 | doi = 10.1186/1471-2148-10-15 | url = http://www.biomedcentral.com/1471-2148/10/15 }}</ref> In regions where rice was cultivated, rice was also fermented into ethanol.<ref name = rice /> The results of increased alcohol availability led to alcoholism and abuse by those able to acquire it, 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 book|last1=Eng|first1=Mimi Y.|title=Alcohol Research and Health|date=2007-01-01|publisher=U.S. Government Printing Office|issn=1535-7414}}</ref> | 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 book|last1=Eng|first1=Mimi Y.|title=Alcohol Research and Health|date=2007-01-01|publisher=U.S. Government Printing Office|issn=1535-7414}}</ref> | ||
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== Discovery == | == Discovery == | ||
[[Image:ladh.jpg|thumb|right| Horse LADH (Liver Alcohol Dehydrogenase)]] | [[Image:ladh.jpg|thumb|right| Horse LADH (Liver Alcohol Dehydrogenase)]] | ||
The first-ever isolated alcohol dehydrogenase (ADH) was purified in 1937 from ''[[Saccharomyces cerevisiae]]'' (brewer's yeast).<ref>{{cite journal |title= | The first-ever isolated alcohol dehydrogenase (ADH) was purified in 1937 from ''[[Saccharomyces cerevisiae]]'' (brewer's yeast).<ref>{{cite journal |title=Diphosphopyridinproteid ackohol, acetaldehyd|vauthors = Negelein E, Wulff HJ | journal = Biochem. Z. | year = 1937 | volume = 293 | page = 351 }}</ref> Many aspects of the [[catalytic]] mechanism for the horse liver ADH enzyme were investigated by Hugo Theorell and coworkers.<ref name="pmid13920552">{{cite journal | vauthors = Theorell H, McKEE JS | title = Mechanism of action of liver alcohol dehydrogenase | journal = Nature | volume = 192 | issue = 4797 | pages = 47–50 | date = October 1961 | pmid = 13920552 | doi = 10.1038/192047a0 }}</ref> ADH was also one of the first oligomeric enzymes that had its amino acid sequence and three-dimensional structure determined.<ref name="pmid5462776">{{cite journal | vauthors = Jörnvall H, Harris JI | title = Horse liver alcohol dehydrogenase. On the primary structure of the ethanol-active isoenzyme | journal = European Journal of Biochemistry | volume = 13 | issue = 3 | pages = 565–76 | date = April 1970 | pmid = 5462776 | doi = 10.1111/j.1432-1033.1970.tb00962.x }}</ref><ref name="pmid4365379">{{cite journal | vauthors = Brändén CI, Eklund H, Nordström B, Boiwe T, Söderlund G, Zeppezauer E, Ohlsson I, Akeson A | title = Structure of liver alcohol dehydrogenase at 2.9-angstrom resolution | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 70 | issue = 8 | pages = 2439–42 | date = August 1973 | pmid = 4365379 | pmc = 433752 | doi = 10.1073/pnas.70.8.2439 }}</ref><ref name="isbn978-91-7409-567-8">{{cite book | author = Hellgren M | title = Enzymatic studies of alcohol dehydrogenase by a combination of in vitro and in silico methods, Ph.D. thesis | publisher = Karolinska Institutet | location = Stockholm, Sweden | year = 2009 | page = 70 | isbn = 978-91-7409-567-8 | oclc = | doi = | url = http://diss.kib.ki.se/2009/978-91-7409-567-8/thesis.pdf | access-date = }}</ref> | ||
In early 1960, it was discovered in fruit flies of the genus ''[[Drosophila]]''.<ref name="Sofer">{{cite journal | vauthors = Sofer W, Martin PF | title = Analysis of alcohol dehydrogenase gene expression in Drosophila | journal = Annual Review of Genetics | volume = 21 | issue = | pages = 203–25 | year = 1987 | pmid = 3327463 | doi = 10.1146/annurev.ge.21.120187.001223 }}</ref> | In early 1960, it was discovered in fruit flies of the genus ''[[Drosophila]]''.<ref name="Sofer">{{cite journal | vauthors = Sofer W, Martin PF | title = Analysis of alcohol dehydrogenase gene expression in Drosophila | journal = Annual Review of Genetics | volume = 21 | issue = | pages = 203–25 | year = 1987 | pmid = 3327463 | doi = 10.1146/annurev.ge.21.120187.001223 }}</ref> | ||
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== Active site == | == Active site == | ||
[[Image:active site3.jpg|thumb|The active site of alcohol dehydrogenase]] | [[Image:active site3.jpg|thumb|The active site of alcohol dehydrogenase]] | ||
The active site of human ADH1 (PDB:1HSO) consists of a zinc atom, His-67, Cys-174, Cys-46, Thr-48, His-51, Ile-269, Val-292, Ala-317, and | The active site of human ADH1 (PDB:1HSO) consists of a zinc atom, His-67, Cys-174, Cys-46, Thr-48, His-51, Ile-269, Val-292, Ala-317, and Phe-319. In the commonly studied horse liver isoform, Thr-48 is a Ser, and Leu-319 is a Phe. The zinc coordinates the substrate (alcohol). The zinc is coordinated by Cys-46, Cys-174, and His-67. Leu-319, Ala-317, His-51, Ile-269 and Val-292 stabilize NAD<sup>+</sup> by forming [[hydrogen bonds]]. His-51 and Ile-269 form hydrogen bonds with the alcohols on nicotinamide ribose. Phe-319, Ala-317 and Val-292 form hydrogen bonds with the amide on NAD<sup>+</sup>.<ref name="Hammes" /> | ||
== Structural zinc site == | == Structural zinc site == | ||
[[Image:Zinc interaction Cysteine.jpg|thumb|The structural zinc binding motif in alcohol dehydrogenase from a MD simulation]] | [[Image:Zinc interaction Cysteine.jpg|thumb|The structural zinc binding motif in alcohol dehydrogenase from a MD simulation]] | ||
Mammalian alcohol dehydrogenases also have a structural zinc site. This Zn ion plays a structural role and is crucial for protein stability. The structures of the catalytic and structural zinc sites in horse liver alcohol dehydrogenase (HLADH) as revealed in crystallographic structures, which has been studied computationally with quantum chemical as well as with classical molecular dynamics methods. The structural zinc site is composed of four closely spaced cysteine ligands (Cys97, Cys100, Cys103, and Cys111 in the amino acid sequence) positioned in an almost symmetric tetrahedron around the Zn ion. A recent study showed that the interaction between zinc and cysteine is governed by primarily an electrostatic contribution with an additional covalent contribution to the binding.<ref name="pmid19177216">{{cite journal | vauthors = Brandt EG, Hellgren M, Brinck T, Bergman T, Edholm O | title = Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site | journal = Physical Chemistry Chemical Physics | volume = 11 | issue = 6 | pages = 975–83 | date = | Mammalian alcohol dehydrogenases also have a structural zinc site. This Zn ion plays a structural role and is crucial for protein stability. The structures of the catalytic and structural zinc sites in horse liver alcohol dehydrogenase (HLADH) as revealed in crystallographic structures, which has been studied computationally with quantum chemical as well as with classical molecular dynamics methods. The structural zinc site is composed of four closely spaced cysteine ligands (Cys97, Cys100, Cys103, and Cys111 in the amino acid sequence) positioned in an almost symmetric tetrahedron around the Zn ion. A recent study showed that the interaction between zinc and cysteine is governed by primarily an electrostatic contribution with an additional covalent contribution to the binding.<ref name="pmid19177216">{{cite journal | vauthors = Brandt EG, Hellgren M, Brinck T, Bergman T, Edholm O | title = Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site | journal = Physical Chemistry Chemical Physics | volume = 11 | issue = 6 | pages = 975–83 | date = February 2009 | pmid = 19177216 | doi = 10.1039/b815482a }}</ref> | ||
== Types == | == Types == | ||
=== Human === | === Human === | ||
In humans, ADH exists in multiple forms as a dimer and is encoded by at least seven different genes. There are five classes (I-V) of alcohol dehydrogenase, but the [[hepatic]] form that is used primarily in humans is 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 = | In humans, ADH exists in multiple forms as a dimer and is encoded by at least seven different genes. There are five classes (I-V) of alcohol dehydrogenase, but the [[hepatic]] form that is used primarily in humans is 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 }}</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 | 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 }}</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> | :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 | date = | | 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 | date = | website = | 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 <!--DASHBot-->| deadurl= no}}</ref> | ||
Another evolutionary purpose may be metabolism of the endogenous alcohol [[vitamin A]] ([[retinol]]), which generates the hormone [[retinoic acid]], although the function here may be primarily the elimination of toxic levels of retinol.<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 = | Another evolutionary purpose may be metabolism of the endogenous alcohol [[vitamin A]] ([[retinol]]), which generates the hormone [[retinoic acid]], although the function here may be primarily the elimination of toxic levels of retinol.<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 }}</ref> | ||
{| | {| | ||
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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: | 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 |author1=Cox, Michael |author2=Nelson, David R. |author3=Lehninger, Albert L | title = Lehninger Principles of Biochemistry | edition = | publisher = W. H. Freeman | location = San Francisco | year = 2005 | page = 180 | isbn = 0-7167-4339- | : 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 |author1=Cox, Michael |author2=Nelson, David R. |author3=Lehninger, Albert L | title = Lehninger Principles of Biochemistry | edition = | publisher = W. H. Freeman | location = San Francisco | year = 2005 | page = 180 | isbn = 978-0-7167-4339-2 | oclc = | doi = | url =}}</ref> | ||
[[Image:AlcoholDehydrogenase-1A4U.png|thumb|left | Alcohol Dehydrogenase]] | [[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 = | 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 }}</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. | 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. | ||
[[Brewer's yeast]] also has another alcohol dehydrogenase, [[ADH2]], which evolved out of a duplicate version of the chromosome containing the [ | [[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 web | url = https://www.newscientist.com/channel/life/mg19225831.100-festive-special-the-brewers-tale.html | title = Festive special: The brewer's tale - life | author = Coghlan A | date = 23 December 2006 | website = | publisher = New Scientist | pages = | 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<!--DASHBot-->| deadurl= no}}</ref> | ||
===Plants=== | ===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 = | 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 }}</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 | url = http://www.plantphysiol.org/cgi/content/full/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 }}</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 | url = http://www.amjbot.org/cgi/content/abstract/91/11/1834 | archive-url = https://web.archive.org/web/20100526070916/http://www.amjbot.org/cgi/content/abstract/91/11/1834 | deadurl = no | archive-date = 26 May 2010 <!--DASHBot--> }}</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 === | === Iron-containing === | ||
| Line 255: | Line 255: | ||
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}} | 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: | 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 = | *''[[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 }}</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 = | *''[[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 = }}</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 = | * ''[[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 = }}</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 = | * ''[[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 = }}</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 = | * ''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 }}</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 = | *[[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 = }}</ref> | ||
* ''[[Clostridium kluyveri]]'' NAD-dependent [[4-hydroxybutyrate dehydrogenase]] (4hbd) {{EC number|1.1.1.61}} | * ''[[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) | * ''[[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 = | * ''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 = }}</ref> | ||
*''E. coli'' and ''[[Salmonella typhimurium]]'' [[ethanolamine]] utilization [[protein]] eutG. | *''E. coli'' and ''[[Salmonella typhimurium]]'' [[ethanolamine]] utilization [[protein]] eutG. | ||
*''E. coli'' hypothetical protein yiaY. | *''E. coli'' hypothetical protein yiaY. | ||
| Line 274: | Line 274: | ||
In biotransformation, alcohol dehydrogenases are often used for the synthesis of enantiomerically pure stereoisomers of chiral alcohols. Often, high chemo- and enantioselectivity can be achieved. One example is the alcohol dehydrogenase from ''[[Lactobacillus brevis]]'' (''Lb''ADH), which is described to be a versatile biocatalyst.<ref>{{cite journal|vauthors=Leuchs S, Greiner L |title=Alcohol dehydrogenase from ''Lactobacillus brevis'': A versatile catalyst for enenatioselective reduction |journal=CABEQ |pages=267–281 |year=2011 |url=http://www.hdki.hr/cabeq/pdf/25_2_2011/Cabeq_2011_02_13.pdf }}{{dead link|date=June 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The high chemospecificity has been confirmed also in the case of substrates presenting two potential redox sites. For instance [[cinnamaldehyde]] presents both aliphatic double bond and aldehyde function. Unlike conventional catalysts, alcohol dehydrogenases are able to selectively act only on the latter, yielding exclusively [[cinnamyl alcohol]].<ref name="pmid19420690">{{cite journal | vauthors = Zucca P, Littarru M, Rescigno A, Sanjust E | title = Cofactor recycling for selective enzymatic biotransformation of cinnamaldehyde to cinnamyl alcohol | journal = Bioscience, Biotechnology, and Biochemistry | volume = 73 | issue = 5 | pages = 1224–6 | date = May 2009 | pmid = 19420690 | doi = 10.1271/bbb.90025 }}</ref> | In biotransformation, alcohol dehydrogenases are often used for the synthesis of enantiomerically pure stereoisomers of chiral alcohols. Often, high chemo- and enantioselectivity can be achieved. One example is the alcohol dehydrogenase from ''[[Lactobacillus brevis]]'' (''Lb''ADH), which is described to be a versatile biocatalyst.<ref>{{cite journal|vauthors=Leuchs S, Greiner L |title=Alcohol dehydrogenase from ''Lactobacillus brevis'': A versatile catalyst for enenatioselective reduction |journal=CABEQ |pages=267–281 |year=2011 |url=http://www.hdki.hr/cabeq/pdf/25_2_2011/Cabeq_2011_02_13.pdf }}{{dead link|date=June 2017 |bot=InternetArchiveBot |fix-attempted=yes }}</ref> The high chemospecificity has been confirmed also in the case of substrates presenting two potential redox sites. For instance [[cinnamaldehyde]] presents both aliphatic double bond and aldehyde function. Unlike conventional catalysts, alcohol dehydrogenases are able to selectively act only on the latter, yielding exclusively [[cinnamyl alcohol]].<ref name="pmid19420690">{{cite journal | vauthors = Zucca P, Littarru M, Rescigno A, Sanjust E | title = Cofactor recycling for selective enzymatic biotransformation of cinnamaldehyde to cinnamyl alcohol | journal = Bioscience, Biotechnology, and Biochemistry | volume = 73 | issue = 5 | pages = 1224–6 | date = May 2009 | pmid = 19420690 | doi = 10.1271/bbb.90025 }}</ref> | ||
In fuel cells, alcohol dehydrogenases can be used to catalyze the breakdown of fuel for an ethanol [[fuel cell]]. Scientists at [[Saint Louis University]] have used carbon-supported alcohol dehydrogenase with poly([[methylene green]]) as an anode, with a [[nafion]] membrane, to achieve about 50 μ[[ampere|A]]/cm<sup>2</sup>.<ref name="pmid15672138">{{cite journal | vauthors = Moore CM, Minteer SD, Martin RS | title = Microchip-based ethanol/oxygen biofuel cell | journal = Lab on a Chip | volume = 5 | issue = 2 | pages = 218–25 | date = | In fuel cells, alcohol dehydrogenases can be used to catalyze the breakdown of fuel for an ethanol [[fuel cell]]. Scientists at [[Saint Louis University]] have used carbon-supported alcohol dehydrogenase with poly([[methylene green]]) as an anode, with a [[nafion]] membrane, to achieve about 50 μ[[ampere|A]]/cm<sup>2</sup>.<ref name="pmid15672138">{{cite journal | vauthors = Moore CM, Minteer SD, Martin RS | title = Microchip-based ethanol/oxygen biofuel cell | journal = Lab on a Chip | volume = 5 | issue = 2 | pages = 218–25 | date = February 2005 | pmid = 15672138 | doi = 10.1039/b412719f }}</ref> | ||
In 1949, [[Efraim Racker|E. Racker]] defined one unit of alcohol dehydrogenase activity as the amount that causes a change in [[optical density]] of 0.001 per minute under the standard conditions of [[assay]].<ref name="pmid15443900">{{cite journal | vauthors = Racker E | title = Crystalline alcohol dehydrogenase from baker's yeast | journal = | In 1949, [[Efraim Racker|E. Racker]] defined one unit of alcohol dehydrogenase activity as the amount that causes a change in [[optical density]] of 0.001 per minute under the standard conditions of [[assay]].<ref name="pmid15443900">{{cite journal | vauthors = Racker E | title = Crystalline alcohol dehydrogenase from baker's yeast | journal = The Journal of Biological Chemistry | volume = 184 | issue = 1 | pages = 313–9 | date = May 1950 | pmid = 15443900 | doi = }}</ref> Recently, the international definition of enzymatic unit (E.U.) has been more common: one unit of Alcohol Dehydrogenase will convert 1.0 µmole of [[ethanol]] to [[acetaldehyde]] per minute at pH 8.8 at 25 °C.<ref>{{cite web | title = Enzymatic Assay of Alcohol Dehydrogenase (EC 1.1.1.1) | url = http://www.sigmaaldrich.com/technical-documents/protocols/biology/enzymatic-assay-of-alcohol-dehydrogenase.html | publisher = Sigma Aldrich | access-date = 13 July 2015 }}</ref> | ||
== Clinical significance == | == Clinical significance == | ||
| Line 282: | Line 282: | ||
=== Alcoholism === | === Alcoholism === | ||
There have been studies showing that ADH may have an influence on the dependence on [[ethanol metabolism]] in alcoholics. Researchers have tentatively detected a few genes to be associated with alcoholism. If the variants of these genes encode slower metabolizing forms of ADH2 and ADH3, there is increased risk of alcoholism. The studies have found that mutations of ADH2 and ADH3 are related to alcoholism in Northeast Asian populations. However, research continues in order to identify the genes and their influence on alcoholism.<ref name="pmid17716097">{{cite journal | vauthors = Sher KJ, Grekin ER, Williams NA | title = The development of alcohol use disorders | journal = Annual Review of Clinical Psychology | volume = 1 | issue = | pages = 493–523 | year = 2005 | pmid = 17716097 | doi = 10.1146/annurev.clinpsy.1.102803.144107 }}</ref> | There have been studies showing that ADH may have an influence on the dependence on [[ethanol metabolism]] in alcoholics. Researchers have tentatively detected a few genes to be associated with [[alcoholism]]. If the variants of these genes encode slower metabolizing forms of ADH2 and ADH3, there is increased risk of alcoholism. The studies have found that mutations of ADH2 and ADH3 are related to alcoholism in Northeast Asian populations. However, research continues in order to identify the genes and their influence on alcoholism.<ref name="pmid17716097">{{cite journal | vauthors = Sher KJ, Grekin ER, Williams NA | title = The development of alcohol use disorders | journal = Annual Review of Clinical Psychology | volume = 1 | issue = | pages = 493–523 | year = 2005 | pmid = 17716097 | doi = 10.1146/annurev.clinpsy.1.102803.144107 }}</ref> | ||
On the other hand, it seems that there have been mutations in ADH that have been naturally selected because they protect against alcoholism. It could be that they speed up the conversion of alcohol into [[acetaldehyde]] causing drinkers to feel unwell.<ref>{{cite journal | vauthors = Johnson KE, Voight BF | title = Patterns of shared signatures of recent positive selection across human populations | journal = Nature Ecology & Evolution | volume = 2 | issue = 4 | pages = 713–720 | date = April 2018 | pmid = 29459708 | pmc = 5866773 | doi = 10.1038/s41559-018-0478-6 }}</ref><ref>{{cite journal|last1=Andy Coghlan|title=Evolution may stop us drinking alcohol|journal=New Scientist|date=Feb 24, 2018|url=https://www.newscientist.com/article/mg23731663-600-were-evolving-a-gene-that-may-stop-us-from-drinking-alcohol}}</ref> | |||
=== Drug dependence === | === Drug dependence === | ||
Drug dependence is another problem associated with ADH, which researchers think might be linked to alcoholism. One particular study suggests that drug dependence has seven ADH genes associated with it. These results may lead to treatments that target these specific genes. However, more research is necessary.<ref name="pmid17185388">{{cite journal | vauthors = Luo X, Kranzler HR, Zuo L, Wang S, Schork NJ, Gelernter J | title = Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans | journal = Human Molecular Genetics | volume = 16 | issue = 4 | pages = 380–90 | date = | Drug dependence is another problem associated with ADH, which researchers think might be linked to alcoholism. One particular study suggests that drug dependence has seven ADH genes associated with it. These results may lead to treatments that target these specific genes. However, more research is necessary.<ref name="pmid17185388">{{cite journal | vauthors = Luo X, Kranzler HR, Zuo L, Wang S, Schork NJ, Gelernter J | title = Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans | journal = Human Molecular Genetics | volume = 16 | issue = 4 | pages = 380–90 | date = February 2007 | pmid = 17185388 | pmc = 1853246 | doi = 10.1093/hmg/ddl460 }}</ref> | ||
=== Poisoning === | === Poisoning === | ||
[[Fomepizole]], a drug that inhibits alcohol dehydrogenase, can be used in the setting of acute [[methanol]]<ref>International Programme on Chemical Safety (IPCS): Methanol (PIM 335), [http://www.inchem.org/documents/pims/chemical/pim335.htm#10.%20MANAGEMENT], retrieved on March 1, 2008</ref> or [[ethylene glycol]]<ref name="pmid18072148">{{cite journal|vauthors=Velez LI, Shepherd G, Lee YC, Keyes DC |title=Ethylene glycol ingestion treated only with fomepizole |journal= | [[Fomepizole]], a drug that inhibits alcohol dehydrogenase, can be used in the setting of acute [[methanol]]<ref>International Programme on Chemical Safety (IPCS): Methanol (PIM 335), [http://www.inchem.org/documents/pims/chemical/pim335.htm#10.%20MANAGEMENT], retrieved on March 1, 2008</ref> or [[ethylene glycol]]<ref name="pmid18072148">{{cite journal | vauthors = Velez LI, Shepherd G, Lee YC, Keyes DC | title = Ethylene glycol ingestion treated only with fomepizole | journal = Journal of Medical Toxicology | volume = 3 | issue = 3 | pages = 125–8 | date = September 2007 | pmid = 18072148 | pmc = 3550067 | doi = 10.1007/BF03160922 }}</ref> toxicity. This prevents the conversion of methanol to its toxic metabolites, [[formic acid]] and [[formaldehyde]]. | ||
== See also == | == See also == | ||
| Line 304: | Line 306: | ||
== External links == | == External links == | ||
{{commons category|Alcohol dehydrogenase}} | {{commons category|Alcohol dehydrogenase}} | ||
* [http://www.biochem.ucl.ac.uk/bsm/enzymes/ec1/ec01/ec01/ec0001/index.html PDBsum] has links to three-dimensional structures of various alcohol dehydrogenases contained in the [[Protein Data Bank]] | * [https://web.archive.org/web/20080517055711/http://www.biochem.ucl.ac.uk/bsm/enzymes/ec1/ec01/ec01/ec0001/index.html PDBsum] has links to three-dimensional structures of various alcohol dehydrogenases contained in the [[Protein Data Bank]] | ||
* [http://www.expasy.org/cgi-bin/nicezyme.pl?1.1.1.1 ExPASy] contains links to the alcohol dehydrogenase sequences in [[Swiss-Prot]], to a [[Medline]] literature search about the enzyme, and to entries in other databases. | * [http://www.expasy.org/cgi-bin/nicezyme.pl?1.1.1.1 ExPASy] contains links to the alcohol dehydrogenase sequences in [[Swiss-Prot]], to a [[Medline]] literature search about the enzyme, and to entries in other databases. | ||
Revision as of 10:41, 6 December 2018
| Alcohol dehydrogenase | |||||||||
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| File:Protein ADH5 PDB 1m6h.png | |||||||||
| Identifiers | |||||||||
| EC number | 1.1.1.1 | ||||||||
| CAS number | 9031-72-5 | ||||||||
| Databases | |||||||||
| IntEnz | IntEnz view | ||||||||
| BRENDA | BRENDA entry | ||||||||
| ExPASy | NiceZyme view | ||||||||
| KEGG | KEGG entry | ||||||||
| MetaCyc | metabolic pathway | ||||||||
| PRIAM | profile | ||||||||
| PDB structures | RCSB PDB PDBe PDBsum | ||||||||
| Gene Ontology | AmiGO / QuickGO | ||||||||
| |||||||||
Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that otherwise are toxic, and they also participate in generation of useful aldehyde, ketone, or alcohol groups during biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.
Evolution
Genetic evidence from comparisons of multiple organisms showed that a glutathione-dependent formaldehyde dehydrogenase, identical to a class III alcohol dehydrogenase (ADH-3/ADH5), is presumed to be the ancestral enzyme for the entire ADH family.[2][3][4] 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.[3][4]
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 nitric oxide signaling.[5][6]
In humans, sequencing of the ADH1B gene (responsible for production of an alcohol dehydrogenase polypeptide) shows several functional variants. In one, there is a 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.[7] 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.[7] This provides some protection against excessive alcohol consumption and alcohol dependence (alcoholism)[8][9][10]. 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.[11] In regions where rice was cultivated, rice was also fermented into ethanol.[11] The results of increased alcohol availability led to alcoholism and abuse by those able to acquire it, resulting in lower reproductive fitness.[11] Those with the variant allele have little tolerance for alcohol, thus lowering chance of dependence and abuse.[7][11] 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.[7] 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.[12]
Discovery
The first-ever isolated alcohol dehydrogenase (ADH) was purified in 1937 from Saccharomyces cerevisiae (brewer's yeast).[13] Many aspects of the catalytic mechanism for the horse liver ADH enzyme were investigated by Hugo Theorell and coworkers.[14] ADH was also one of the first oligomeric enzymes that had its amino acid sequence and three-dimensional structure determined.[15][16][17]
In early 1960, it was discovered in fruit flies of the genus Drosophila.[18]
Properties
The alcohol dehydrogenases comprise a group of several isozymes that catalyse the oxidation of primary and secondary alcohols to aldehydes and ketones, respectively, and also can catalyse the reverse reaction.[18] In mammals this is a redox (reduction/oxidation) reaction involving the coenzyme nicotinamide adenine dinucleotide (NAD+).
Oxidation of alcohol
Mechanism of action in humans
Steps
- Binding of the coenzyme NAD+
- Binding of the alcohol substrate by coordination to zinc
- Deprotonation of His-51
- Deprotonation of nicotinamide ribose
- Deprotonation of Thr-48
- Deprotonation of the alcohol
- Hydride transfer from the alkoxide ion to NAD+, leading to NADH and a zinc bound aldehyde or ketone
- Release of the product aldehyde.
The mechanism in yeast and bacteria is the reverse of this reaction. These steps are supported through kinetic studies.[19]
Involved subunits
The substrate is coordinated to the zinc and this enzyme has two zinc atoms per subunit. One is the active site, which is involved in catalysis. In the active site, the ligands are Cys-46, Cys-174, His-67, and one water molecule. The other subunit is involved with structure. In this mechanism, the hydride from the alcohol goes to NAD+. Crystal structures indicate that the His-51 deprotonates the nicotinamide ribose, which deprotonates Ser-48. Finally, Ser-48 deprotonates the alcohol, making it an aldehyde.[19] From a mechanistic perspective, if the enzyme adds hydride to the re face of NAD+, the resulting hydrogen is incorporated into the pro-R position. Enzymes that add hydride to the re face are deemed Class A dehydrogenases.
Active site
The active site of human ADH1 (PDB:1HSO) consists of a zinc atom, His-67, Cys-174, Cys-46, Thr-48, His-51, Ile-269, Val-292, Ala-317, and Phe-319. In the commonly studied horse liver isoform, Thr-48 is a Ser, and Leu-319 is a Phe. The zinc coordinates the substrate (alcohol). The zinc is coordinated by Cys-46, Cys-174, and His-67. Leu-319, Ala-317, His-51, Ile-269 and Val-292 stabilize NAD+ by forming hydrogen bonds. His-51 and Ile-269 form hydrogen bonds with the alcohols on nicotinamide ribose. Phe-319, Ala-317 and Val-292 form hydrogen bonds with the amide on NAD+.[19]
Structural zinc site
Mammalian alcohol dehydrogenases also have a structural zinc site. This Zn ion plays a structural role and is crucial for protein stability. The structures of the catalytic and structural zinc sites in horse liver alcohol dehydrogenase (HLADH) as revealed in crystallographic structures, which has been studied computationally with quantum chemical as well as with classical molecular dynamics methods. The structural zinc site is composed of four closely spaced cysteine ligands (Cys97, Cys100, Cys103, and Cys111 in the amino acid sequence) positioned in an almost symmetric tetrahedron around the Zn ion. A recent study showed that the interaction between zinc and cysteine is governed by primarily an electrostatic contribution with an additional covalent contribution to the binding.[20]
Types
Human
In humans, ADH exists in multiple forms as a dimer and is encoded by at least seven different genes. There are five classes (I-V) of alcohol dehydrogenase, but the hepatic form that is used primarily in humans is class 1. Class 1 consists of α, β, and γ subunits that are encoded by the genes ADH1A, ADH1B, and ADH1C.[21] The enzyme is present at high levels in the liver and the lining of the stomach.[22] It catalyzes the oxidation of ethanol to acetaldehyde (ethanal):
- CH3CH2OH + NAD+ → CH3CHO + NADH + H+
This allows the consumption of alcoholic beverages, but its evolutionary purpose is probably the breakdown of alcohols naturally contained in foods or produced by bacteria in the digestive tract.[23]
Another evolutionary purpose may be metabolism of the endogenous alcohol vitamin A (retinol), which generates the hormone retinoic acid, although the function here may be primarily the elimination of toxic levels of retinol.[24][25]
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Alcohol dehydrogenase is also involved in the toxicity of other types of alcohol: For instance, it oxidizes methanol to produce formaldehyde and ethylene glycol to ultimately yield glycolic and oxalic acids. Humans have at least six slightly different alcohol dehydrogenases. Each is a dimer (i.e., consists of two polypeptides), with each dimer containing two zinc ions Zn2+. 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.
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.[26] The level of activity may not be dependent only on level of expression but also on 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.
Yeast and bacteria
Unlike humans, yeast and bacteria (except lactic acid bacteria, and 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 CO2 + 2 ATP + 2 H2O[27]
In yeast[28] 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+, 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.
Brewer's yeast also has another alcohol dehydrogenase, ADH2, which evolved out of a duplicate version of the chromosome containing the ADH1 gene. 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.[29]
Plants
In plants, ADH catalyses the same reaction as in yeast and bacteria to ensure that there is a constant supply of NAD+. 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.[30] 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.[31] 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.[32] Differences in the sequences of ADH in different species have been used to create phylogenies showing how closely related different species of plants are.[33] 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.[32]
Iron-containing
| Iron-containing alcohol dehydrogenase | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| File:PDB 1jqa EBI.jpg bacillus stearothermophilus glycerol dehydrogenase complex with glycerol | |||||||||
| Identifiers | |||||||||
| Symbol | Fe-ADH | ||||||||
| Pfam | PF00465 | ||||||||
| Pfam clan | CL0224 | ||||||||
| InterPro | IPR001670 | ||||||||
| PROSITE | PDOC00059 | ||||||||
| SCOP | 1jqa | ||||||||
| SUPERFAMILY | 1jqa | ||||||||
| |||||||||
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] Members of the iron-containing alcohol dehydrogenase family include:
- Saccharomyces cerevisiae alcohol dehydrogenase 4 (gene ADH4)[34]
- Zymomonas mobilis alcohol dehydrogenase 2 (gene adhB)[35]
- Escherichia coli propanediol oxidoreductase EC 1.1.1.77 (gene fucO),[36] 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 1.1.1.- (genes adh1, bdhA and bdhB),[37] enzymes that have activity using butanol and ethanol as substrates.
- E. coli adhE,[38] an iron-dependent enzyme that harbours three different activities: alcohol dehydrogenase, acetaldehyde dehydrogenase (acetylating) EC 1.2.1.10 and pyruvate-formate-lyase deactivase.
- Bacterial glycerol dehydrogenase EC 1.1.1.6 (gene gldA or dhaD).[39]
- Clostridium kluyveri NAD-dependent 4-hydroxybutyrate dehydrogenase (4hbd) EC 1.1.1.61
- Citrobacter freundii and Klebsiella pneumoniae 1,3-propanediol dehydrogenase EC 1.1.1.202 (gene dhaT)
- Bacillus methanolicus NAD-dependent methanol dehydrogenase EC 1.1.1.244[40]
- 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.
Applications
In biotransformation, alcohol dehydrogenases are often used for the synthesis of enantiomerically pure stereoisomers of chiral alcohols. Often, high chemo- and enantioselectivity can be achieved. One example is the alcohol dehydrogenase from Lactobacillus brevis (LbADH), which is described to be a versatile biocatalyst.[41] The high chemospecificity has been confirmed also in the case of substrates presenting two potential redox sites. For instance cinnamaldehyde presents both aliphatic double bond and aldehyde function. Unlike conventional catalysts, alcohol dehydrogenases are able to selectively act only on the latter, yielding exclusively cinnamyl alcohol.[42]
In fuel cells, alcohol dehydrogenases can be used to catalyze the breakdown of fuel for an ethanol fuel cell. Scientists at Saint Louis University have used carbon-supported alcohol dehydrogenase with poly(methylene green) as an anode, with a nafion membrane, to achieve about 50 μA/cm2.[43]
In 1949, E. Racker defined one unit of alcohol dehydrogenase activity as the amount that causes a change in optical density of 0.001 per minute under the standard conditions of assay.[44] Recently, the international definition of enzymatic unit (E.U.) has been more common: one unit of Alcohol Dehydrogenase will convert 1.0 µmole of ethanol to acetaldehyde per minute at pH 8.8 at 25 °C.[45]
Clinical significance
Alcoholism
There have been studies showing that ADH may have an influence on the dependence on ethanol metabolism in alcoholics. Researchers have tentatively detected a few genes to be associated with alcoholism. If the variants of these genes encode slower metabolizing forms of ADH2 and ADH3, there is increased risk of alcoholism. The studies have found that mutations of ADH2 and ADH3 are related to alcoholism in Northeast Asian populations. However, research continues in order to identify the genes and their influence on alcoholism.[46]
On the other hand, it seems that there have been mutations in ADH that have been naturally selected because they protect against alcoholism. It could be that they speed up the conversion of alcohol into acetaldehyde causing drinkers to feel unwell.[47][48]
Drug dependence
Drug dependence is another problem associated with ADH, which researchers think might be linked to alcoholism. One particular study suggests that drug dependence has seven ADH genes associated with it. These results may lead to treatments that target these specific genes. However, more research is necessary.[49]
Poisoning
Fomepizole, a drug that inhibits alcohol dehydrogenase, can be used in the setting of acute methanol[50] or ethylene glycol[51] toxicity. This prevents the conversion of methanol to its toxic metabolites, formic acid and formaldehyde.
See also
- Alcohol dehydrogenase (NAD(P)+)
- Aldehyde dehydrogenase
- Oxidoreductase
- Blood alcohol content for rates of metabolism
References
- ↑ PDB: 1m6h; Sanghani PC, Robinson H, Bosron WF, Hurley TD (September 2002). "Human glutathione-dependent formaldehyde dehydrogenase. Structures of apo, binary, and inhibitory ternary complexes". Biochemistry. 41 (35): 10778–86. doi:10.1021/bi0257639. PMID 12196016.
- ↑ Gutheil WG, Holmquist B, Vallee BL (January 1992). "Purification, characterization, and partial sequence of the glutathione-dependent formaldehyde dehydrogenase from Escherichia coli: a class III alcohol dehydrogenase". Biochemistry. 31 (2): 475–81. doi:10.1021/bi00117a025. PMID 1731906.
- ↑ 3.0 3.1 Danielsson O, Jörnvall H (October 1992). ""Enzymogenesis": classical liver alcohol dehydrogenase origin from the glutathione-dependent formaldehyde dehydrogenase line". Proceedings of the National Academy of Sciences of the United States of America. 89 (19): 9247–51. doi:10.1073/pnas.89.19.9247. PMC 50103. PMID 1409630.
- ↑ 4.0 4.1 Persson B, Hedlund J, Jörnvall H (December 2008). "Medium- and short-chain dehydrogenase/reductase gene and protein families : the MDR superfamily". Cellular and Molecular Life Sciences. 65 (24): 3879–94. doi:10.1007/s00018-008-8587-z. PMC 2792335. PMID 19011751.
- ↑ Staab CA, Hellgren M, Höög JO (December 2008). "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". Cellular and Molecular Life Sciences. 65 (24): 3950–60. doi:10.1007/s00018-008-8592-2. PMID 19011746.
- ↑ Godoy L, Gonzàlez-Duarte R, Albalat R (2006). "S-Nitrosogluthathione reductase activity of amphioxus ADH3: insights into the nitric oxide metabolism". International Journal of Biological Sciences. 2 (3): 117–24. doi:10.7150/ijbs.2.117. PMC 1458435. PMID 16763671.
- ↑ 7.0 7.1 7.2 7.3 Whitfield, John B. "ADH and ALDH genotypes in relation to alcohol metabolic rate and sensitivity" (PDF). Alcohol and Alcoholism.[permanent dead link]
- ↑ Thomasson HR, Edenberg HJ, Crabb DW, Mai XL, Jerome RE, Li TK, Wang SP, Lin YT, Lu RB, Yin SJ (April 1991). "Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men". American Journal of Human Genetics. 48 (4): 677–81. PMC 1682953. PMID 2014795.
- ↑ Edenberg HJ, McClintick JN (October 2018). "Alcohol dehydrogenases, aldehyde dehydrogenases and alcohol use disorders: a critical review". Alcoholism, Clinical and Experimental Research. doi:10.1111/acer.13904. PMID 30320893.
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- ↑ 11.0 11.1 11.2 11.3 Peng Y, Shi H, Qi XB, Xiao CJ, Zhong H, Ma RL, Su B (January 2010). "The ADH1B Arg47His polymorphism in east Asian populations and expansion of rice domestication in history". BMC Evolutionary Biology. 10: 15. doi:10.1186/1471-2148-10-15. PMC 2823730. PMID 20089146.
- ↑ Eng, Mimi Y. (2007-01-01). Alcohol Research and Health. U.S. Government Printing Office. ISSN 1535-7414.
- ↑ Negelein E, Wulff HJ (1937). "Diphosphopyridinproteid ackohol, acetaldehyd". Biochem. Z. 293: 351.
- ↑ Theorell H, McKEE JS (October 1961). "Mechanism of action of liver alcohol dehydrogenase". Nature. 192 (4797): 47–50. doi:10.1038/192047a0. PMID 13920552.
- ↑ Jörnvall H, Harris JI (April 1970). "Horse liver alcohol dehydrogenase. On the primary structure of the ethanol-active isoenzyme". European Journal of Biochemistry. 13 (3): 565–76. doi:10.1111/j.1432-1033.1970.tb00962.x. PMID 5462776.
- ↑ Brändén CI, Eklund H, Nordström B, Boiwe T, Söderlund G, Zeppezauer E, Ohlsson I, Akeson A (August 1973). "Structure of liver alcohol dehydrogenase at 2.9-angstrom resolution". Proceedings of the National Academy of Sciences of the United States of America. 70 (8): 2439–42. doi:10.1073/pnas.70.8.2439. PMC 433752. PMID 4365379.
- ↑ Hellgren M (2009). Enzymatic studies of alcohol dehydrogenase by a combination of in vitro and in silico methods, Ph.D. thesis (PDF). Stockholm, Sweden: Karolinska Institutet. p. 70. ISBN 978-91-7409-567-8.
- ↑ 18.0 18.1 Sofer W, Martin PF (1987). "Analysis of alcohol dehydrogenase gene expression in Drosophila". Annual Review of Genetics. 21: 203–25. doi:10.1146/annurev.ge.21.120187.001223. PMID 3327463.
- ↑ 19.0 19.1 19.2 Hammes-Schiffer S, Benkovic SJ (2006). "Relating protein motion to catalysis". Annual Review of Biochemistry. 75: 519–41. doi:10.1146/annurev.biochem.75.103004.142800. PMID 16756501.
- ↑ Brandt EG, Hellgren M, Brinck T, Bergman T, Edholm O (February 2009). "Molecular dynamics study of zinc binding to cysteines in a peptide mimic of the alcohol dehydrogenase structural zinc site". Physical Chemistry Chemical Physics. 11 (6): 975–83. doi:10.1039/b815482a. PMID 19177216.
- ↑ Sultatos LG, Pastino GM, Rosenfeld CA, Flynn EJ (March 2004). "Incorporation of the genetic control of alcohol dehydrogenase into a physiologically based pharmacokinetic model for ethanol in humans". Toxicological Sciences. 78 (1): 20–31. doi:10.1093/toxsci/kfh057. PMID 14718645.
- ↑ Farrés J, Moreno A, Crosas B, Peralba JM, Allali-Hassani A, Hjelmqvist L, Jörnvall H, Parés X (September 1994). "Alcohol dehydrogenase of class IV (sigma sigma-ADH) from human stomach. cDNA sequence and structure/function relationships". European Journal of Biochemistry. 224 (2): 549–57. doi:10.1111/j.1432-1033.1994.00549.x. PMID 7925371.
- ↑ Kovacs B, Stöppler MC. "Alcohol and Nutrition". MedicineNet, Inc. Archived from the original on 23 June 2011. Retrieved 2011-06-07.
- ↑ Duester G (September 2008). "Retinoic acid synthesis and signaling during early organogenesis". Cell. 134 (6): 921–31. doi:10.1016/j.cell.2008.09.002. PMC 2632951. PMID 18805086.
- ↑ Hellgren M, Strömberg P, Gallego O, Martras S, Farrés J, Persson B, Parés X, Höög JO (February 2007). "Alcohol dehydrogenase 2 is a major hepatic enzyme for human retinol metabolism". Cellular and Molecular Life Sciences. 64 (4): 498–505. doi:10.1007/s00018-007-6449-8. PMID 17279314.
- ↑ Parlesak A, Billinger MH, Bode C, Bode JC (2002). "Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a caucasian population". Alcohol and Alcoholism. 37 (4): 388–93. doi:10.1093/alcalc/37.4.388. PMID 12107043.
- ↑ Cox, Michael; Nelson, David R.; Lehninger, Albert L (2005). Lehninger Principles of Biochemistry. San Francisco: W. H. Freeman. p. 180. ISBN 978-0-7167-4339-2.
- ↑ Leskovac V, Trivić S, Pericin D (December 2002). "The three zinc-containing alcohol dehydrogenases from baker's yeast, Saccharomyces cerevisiae". FEMS Yeast Research. 2 (4): 481–94. doi:10.1111/j.1567-1364.2002.tb00116.x. PMID 12702265.
- ↑ Coghlan A (23 December 2006). "Festive special: The brewer's tale - life". New Scientist. Archived from the original on 15 September 2008. Retrieved 2009-04-27.
- ↑ Chang C, Meyerowitz EM (March 1986). "Molecular cloning and DNA sequence of the Arabidopsis thaliana alcohol dehydrogenase gene". Proceedings of the National Academy of Sciences of the United States of America. 83 (5): 1408–12. doi:10.1073/pnas.83.5.1408. PMC 323085. PMID 2937058.
- ↑ Chung HJ, Ferl RJ (October 1999). "Arabidopsis alcohol dehydrogenase expression in both shoots and roots is conditioned by root growth environment". Plant Physiology. 121 (2): 429–36. doi:10.1104/pp.121.2.429. PMC 59405. PMID 10517834.
- ↑ 32.0 32.1 Thompson CE, Fernandes CL, de Souza ON, de Freitas LB, Salzano FM (May 2010). "Evaluation of the impact of functional diversification on Poaceae, Brassicaceae, Fabaceae, and Pinaceae alcohol dehydrogenase enzymes". Journal of Molecular Modeling. 16 (5): 919–28. doi:10.1007/s00894-009-0576-0. PMID 19834749.
- ↑ Järvinen P, Palmé A, Orlando Morales L, Lännenpää M, Keinänen M, Sopanen T, Lascoux M (November 2004). "Phylogenetic relationships of Betula species (Betulaceae) based on nuclear ADH and chloroplast matK sequences". American Journal of Botany. 91 (11): 1834–45. doi:10.3732/ajb.91.11.1834. PMID 21652331. Archived from the original on 26 May 2010.
- ↑ Williamson VM, Paquin CE (September 1987). "Homology of Saccharomyces cerevisiae ADH4 to an iron-activated alcohol dehydrogenase from Zymomonas mobilis". Molecular & General Genetics. 209 (2): 374–81. doi:10.1007/bf00329668. PMID 2823079.
- ↑ Conway T, Sewell GW, Osman YA, Ingram LO (June 1987). "Cloning and sequencing of the alcohol dehydrogenase II gene from Zymomonas mobilis". Journal of Bacteriology. 169 (6): 2591–7. PMC 212129. PMID 3584063.
- ↑ Conway T, Ingram LO (July 1989). "Similarity of Escherichia coli propanediol oxidoreductase (fucO product) and an unusual alcohol dehydrogenase from Zymomonas mobilis and Saccharomyces cerevisiae". Journal of Bacteriology. 171 (7): 3754–9. PMC 210121. PMID 2661535.
- ↑ Walter KA, Bennett GN, Papoutsakis ET (November 1992). "Molecular characterization of two Clostridium acetobutylicum ATCC 824 butanol dehydrogenase isozyme genes". Journal of Bacteriology. 174 (22): 7149–58. PMC 207405. PMID 1385386.
- ↑ Kessler D, Leibrecht I, Knappe J (April 1991). "Pyruvate-formate-lyase-deactivase and acetyl-CoA reductase activities of Escherichia coli reside on a polymeric protein particle encoded by adhE". FEBS Letters. 281 (1–2): 59–63. doi:10.1016/0014-5793(91)80358-A. PMID 2015910.
- ↑ Truniger V, Boos W (March 1994). "Mapping and cloning of gldA, the structural gene of the Escherichia coli glycerol dehydrogenase". Journal of Bacteriology. 176 (6): 1796–800. PMC 205274. PMID 8132480.
- ↑ de Vries GE, Arfman N, Terpstra P, Dijkhuizen L (August 1992). "Cloning, expression, and sequence analysis of the Bacillus methanolicus C1 methanol dehydrogenase gene". Journal of Bacteriology. 174 (16): 5346–53. PMC 206372. PMID 1644761.
- ↑ Leuchs S, Greiner L (2011). "Alcohol dehydrogenase from Lactobacillus brevis: A versatile catalyst for enenatioselective reduction" (PDF). CABEQ: 267–281.[permanent dead link]
- ↑ Zucca P, Littarru M, Rescigno A, Sanjust E (May 2009). "Cofactor recycling for selective enzymatic biotransformation of cinnamaldehyde to cinnamyl alcohol". Bioscience, Biotechnology, and Biochemistry. 73 (5): 1224–6. doi:10.1271/bbb.90025. PMID 19420690.
- ↑ Moore CM, Minteer SD, Martin RS (February 2005). "Microchip-based ethanol/oxygen biofuel cell". Lab on a Chip. 5 (2): 218–25. doi:10.1039/b412719f. PMID 15672138.
- ↑ Racker E (May 1950). "Crystalline alcohol dehydrogenase from baker's yeast". The Journal of Biological Chemistry. 184 (1): 313–9. PMID 15443900.
- ↑ "Enzymatic Assay of Alcohol Dehydrogenase (EC 1.1.1.1)". Sigma Aldrich. Retrieved 13 July 2015.
- ↑ Sher KJ, Grekin ER, Williams NA (2005). "The development of alcohol use disorders". Annual Review of Clinical Psychology. 1: 493–523. doi:10.1146/annurev.clinpsy.1.102803.144107. PMID 17716097.
- ↑ Johnson KE, Voight BF (April 2018). "Patterns of shared signatures of recent positive selection across human populations". Nature Ecology & Evolution. 2 (4): 713–720. doi:10.1038/s41559-018-0478-6. PMC 5866773. PMID 29459708.
- ↑ Andy Coghlan (Feb 24, 2018). "Evolution may stop us drinking alcohol". New Scientist.
- ↑ Luo X, Kranzler HR, Zuo L, Wang S, Schork NJ, Gelernter J (February 2007). "Multiple ADH genes modulate risk for drug dependence in both African- and European-Americans". Human Molecular Genetics. 16 (4): 380–90. doi:10.1093/hmg/ddl460. PMC 1853246. PMID 17185388.
- ↑ International Programme on Chemical Safety (IPCS): Methanol (PIM 335), [1], retrieved on March 1, 2008
- ↑ Velez LI, Shepherd G, Lee YC, Keyes DC (September 2007). "Ethylene glycol ingestion treated only with fomepizole". Journal of Medical Toxicology. 3 (3): 125–8. doi:10.1007/BF03160922. PMC 3550067. PMID 18072148.
External links
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Wikimedia Commons has media related to Alcohol dehydrogenase. |
- PDBsum has links to three-dimensional structures of various alcohol dehydrogenases contained in the Protein Data Bank
- ExPASy contains links to the alcohol dehydrogenase sequences in Swiss-Prot, to a Medline literature search about the enzyme, and to entries in other databases.
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