Alcohol dehydrogenase
Alcohol dehydrogenase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Alcohol dehydrogenases (ADH) (
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
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.
Discovery
The first-ever isolated alcohol dehydrogenase (ADH) was purified in 1937 from
In early 1960, the alcohol dehydrogenase (ADH) gene was discovered in fruit flies of the genus
Properties
The alcohol dehydrogenases comprise a group of several
Mechanism of action in humans
Steps
- Binding of the coenzyme NAD+
- Binding of the alcohol substrate by coordination to zinc(II) ion
- 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 aldehyde.
The mechanism in yeast and bacteria is the reverse of this reaction. These steps are supported through kinetic studies.[27]
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.
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
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 chemistry 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.[28]
Types
Human
In humans, ADH exists in multiple forms as a
- CH3CH2OH + NAD+ → CH3CHO + NADH+ H+
This allows the consumption of
Another evolutionary purpose is reversible metabolism of
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Alcohol dehydrogenase is also involved in the toxicity of other types of alcohol: For instance, it oxidizes
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.[37] 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.
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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[38]
In
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.
Plants
In plants, ADH catalyses the same reaction as in yeast and bacteria to ensure that there is a constant supply of NAD+.
Iron-containing
Iron-containing alcohol dehydrogenase | |||||||||
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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)[45]
- Zymomonas mobilis alcohol dehydrogenase 2 (gene adhB)[46]
- Escherichia coli propanediol oxidoreductase EC 1.1.1.77 (gene fucO),[47] an enzyme involved in the metabolism of fucose and which also seems to contain ferrous ion(s).
- substrates.
- E. coli adhE,[49] 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).[50]
- 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[51]
- E. coli and Salmonella typhimurium ethanolamine utilization proteineutG.
- 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
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.[54]
In 1949,
Clinical significance
Alcoholism
There have been studies showing that variations in ADH that influence ethanol metabolism have an impact on the risk of alcohol dependence.[8][9][10][11][57] The strongest effect is due to variations in ADH1B that increase the rate at which alcohol is converted to acetaldehyde. One such variant is most common in individuals from East Asia and the Middle East, another is most common in individuals from Africa.[9] Both variants reduce the risk for alcoholism, but individuals can become alcoholic despite that. Researchers have tentatively detected a few other genes to be associated with alcoholism, and know that there must be many more remaining to be found.[58] Research continues in order to identify the genes and their influence on alcoholism.
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, however, more research is necessary.[59] Alcohol dependence and other drug dependence may share some risk factors, but because alcohol dependence is often comorbid with other drug dependences, the association of ADH with the other drug dependencies may not be causal.
Poisoning
Fomepizole, a drug that competitively inhibits alcohol dehydrogenase, can be used in the setting of acute methanol[60] or ethylene glycol[61] toxicity. This prevents the conversion of the methanol or ethylene glycol to its toxic metabolites (such as formic acid, formaldehyde, or glycolate). The same effect is also sometimes achieved with ethanol, again by competitive inhibition of ADH.
Drug metabolism
The drug hydroxyzine is broken into its active metabolite cetirizine by alcohol dehydrogenase. Other drugs with alcohol groups may be metabolized in a similar way as long as steric hindrance does not prevent the alcohol from reaching the active site.[62]
See also
- Alcohol dehydrogenase (NAD(P)+)
- Aldehyde dehydrogenase
- Oxidoreductase
- Blood alcohol content for rates of metabolism
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External links
- 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 Medlineliterature search about the enzyme, and to entries in other databases.
- PDBe-KB provides an overview of all the structure information available in the PDB for Alcohol dehydrogenase 1A.
- PDBe-KB provides an overview of all the structure information available in the PDB for Alcohol dehydrogenase 1B.
- PDBe-KB provides an overview of all the structure information available in the PDB for Alcohol dehydrogenase 1C.
- PDBe-KB provides an overview of all the structure information available in the PDB for Alcohol dehydrogenase 4.
- PDBe-KB provides an overview of all the structure information available in the PDB for Alcohol dehydrogenase class-3.