Enzymes for Research, Diagnostic and Industrial Use

Alcohol dehydrogenase

Official Full Name
Alcohol dehydrogenase
Alcohol dehydrogenases (ADH) 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+.
aldehyde reductase; ADH; alcohol dehydrogenase (NAD); aliphatic alcohol dehydrogenase; ethanol dehydrogenase; NAD-dependent alcohol dehydrogenase; NAD-specific aromatic alcohol dehydrogenase; NADH-alcohol dehydrogenase; NADH-aldehyde dehydrogenase; primary alcohol dehydrogenase; yeast alcohol dehydrogenase; EC

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Alcohol dehydrogenases (ADH, EC occurring in many organisms can facilitate the conversion of alcohols primary and secondary alcohols to aldehydes and ketones, respectively, involving the reduction of coenzyme nicotinamide adenine dinucleotide (NAD+). In humans and many other animals, ADHs are able to break down alcohols that are toxic, and also take effect in the production of critical aldehyde or ketone during the biosynthesis of various metabolites, while some alcohol dehydrogenases in plants, yeast, and many bacteria, participate in the catalyzation of the reverse reation in a form of fermentation to ensure a constant supply of NAD+. ADH is also one of the first oligomeric enzymes with three-dimensional structure and amino acid sequence determined.

Alcohol dehydrogenase

Various Types

a. Humans

Human ADH exists as a dimer in multiple forms and is encoded by at least seven different genes. ADH has five classes (I-V). Class 1 is composed of α, β, and γ subunits that are encoded by the genes ADH1A, ADH1B, and ADH1C and it is used primarily in humans as a hepatic form. The enzyme is expressed with high levels in liver and the lining of stomach. It catalyzes the following reaction:

Alcohol dehydrogenaseFigure 1. Reaction catalyzed by human ADH.

One evolutionary purpose of this catalyzation is probably the degradation of alcohols that are naturally contained in foods or produced by bacteria in the digestive tract. Another purpose may be the metabolism of the endogenous alcohol vitamin A, thus generating hormone retinoic acid to eliminate toxic levels of retinol. The human genes encoding class II, III, IV, and V ADH are ADH4, ADH5, ADH7, and ADH6, respectively. The activity level is not only dependent on level of expression but also on allelic diversity among people.

b. Yeast and Bacteria

Being different from humans, yeast and bacteria instead ferment glucose to ethanol and CO2 by utilization of ADH. The overall reaction is shown below:

Alcohol dehydrogenaseFigure 2. Reaction catalyzed by ADH from yeast and bacteria.

In yeast and many bacteria, ADH is of great significance in fermentation, where pyruvate produced from glycolysis is converted to acetaldehyde and carbon dioxide, and the acetaldehyde is then reduced to ethanol by an enzyme ADH1. The latter step is conducted to regenerate NAD+, which is able to maintain the energy-generating glycolysis. Yeasts can produce and consume their own alcohol, while humans exploit yeast to ferment various fruits or grains with the purpose of producing alcoholic beverages. The main alcohol dehydrogenase consisting of four subunits in yeast is larger than the human one.

c. Plants

ADH in plants catalyzes the same reaction as in yeast and bacteria to ensure the constant supply of NAD+. Arabidopsis thaliana contains only one ADH gene and its ADH structure is 47%-conserved, as compared to ADH from horse liver. However, structurally and functionally important residues, such as the seven residues providing ligands for the catalytic and noncatalytic zinc atoms, are conserved. ADH is constitutively present at low levels in the roots of young plants, while its expression increases significantly in the roots lacking oxygen and could also be ameliorated in response to dehydration, low temperatures, and abscisic acid. Plant ADH is critical for fruit ripening, seedlings development, and pollen development.

d. Iron-containing

Another kind of ADHs, unrelated to the above enzymes, is iron-containing ones, which occur in bacteria and fungi and are oxygen-sensitive.

e. Other Types

A further class of ADHs pertains to quinoenzymes that require quinoid cofactors as enzyme-bound electron acceptors. A typical example in this type is methanol dehydrogenase of methylotrophic bacteria.

Mechanism of Action in Humans

First, ADH binds with the coenzyme NAD+. Secondly, ADH binds with the alcohol substrate by coordination to zinc. Thirdly, sequential deprotonation of His-51, nicotinamide ribose, Thr-48 and alcohol is conducted. Next, hydride is transferred from the alkoxide ion to NAD+, which leads to NADH and a zinc bound aldehyde or ketone. Ultimately, the product aldehyde is released. These steps are supported by kinetic studies. The mechanism in yeast and bacteria works in an opposite way.

The substrate is coordinated to the zinc. ADH contains two zinc atoms per subunit, one of which is the active site involving in catalysis. Cys-46, Cys-174, His-67, and one water molecule function as ligands in the active site. Another subunit is related with structure. It has been indicated that the His-51 deprotonates the nicotinamide ribose, which then implements the deprotonation of Thr-48. Eventually, alcohol is deprotonated by Thr-48 residue to obtain the aldehyde.

Structural Zinc Site

ADHs from mammals possess a structural zinc site, which is crucial for protein stability. The crystallographic structures of the catalytic and structural zinc sites in horse liver alcohol dehydrogenase (HLADH) have been computationally researched through quantum chemistry as well as classical molecular dynamics methods. The structural zinc site constitutes four adjacent cysteine ligands of Cys97, Cys100, Cys103, and Cys111, which are positioned in an almost symmetric tetrahedron around the Zn ion. Studies have recently demonstrated that the interaction between zinc and cysteine is primarily determined by an electrostatic interaction that shows an additional covalent contribution to this binding.

Alcohol dehydrogenaseFigure 3. The structural zinc binding motif in alcohol dehydrogenase. (Parlesak A; et al. 2002)


In biotransformation, ADHs are frequently applied in the synthesis of enantiomerically pure stereoisomers of chiral alcohols with high chemo- and enantioselectivity. Alcohol dehydrogenase from Lactobacillus brevis is considered to be a versatile biocatalyst, which could achieve high chemospecificity in the case of substrates bearing two potential redox sites. Alcohol dehydrogenases can also be used to catalyze the digestion of fuel for an ethanol fuel cell.

Clinical significance

In alcoholism, ADH may influence the dependence on ethanol metabolism in alcoholics. It has been tentatively detected that a few genes are associated with alcoholism. There is increased possibility of alcoholism when the variants of these genes encode slower metabolizing forms of ADH2 and ADH3. Mutations of ADH2 and ADH3 have been revealed to be related with alcoholism in Northeast Asian populations. Research are still being continued to identify the genes and their influence on alcoholism. Moreover, ADH mutations that have been naturally selected seem to appear since they protect against alcoholism. It could be that they accelerate the oxidization of alcohol into acetaldehyde that causes drinkers to feel unwell.

Drug dependence is another problem accompanied with ADH, which might be related with alcoholism. It has been suggests that drug dependence has seven associated ADH genes, which is a guidance for treatments targeting these specific genes.

Fomepizole, a drug inhibiting alcohol dehydrogenase, can be applied in the context of acute methanol or ethylene glycol toxication to prevent the production of toxic metabolites, formic acid and formaldehyde.


  1. Parlesak A, Billinger M H, Bode C, Bode J C. Gastric alcohol dehydrogenase activity in man: influence of gender, age, alcohol consumption and smoking in a caucasian population. Alcohol Alcoholism, 2002, 37(4):388–393.

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