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Alcohol dehydrogenase

    In the mid-1960s, alcohol dehydrogenase (ADH) was discovered while studying Drosophila melanogaster. Since then, there has been extensive research on the enyzme [1]Alcohol dehydrogenase is a dimer, weighing 80,000 g/mol[2]. Evidence that it is a dimer can be seen in both the pictures to your right. Alcohol dehydrogenases (EC are a group of seven dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of NAD+ to NADH. In humans and many other animals, they serve to break down alcohols which could otherwise be toxic; in yeast and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation.

The CAS number for this type of the enzyme is [9031-72-5].



Alcohol dehydrogenase is responsible for catalyzing alcohols into aldehydes and ketones, and vice versa. It does not work well with primary alcohols. Instead, it works the best with secondary and cyclic alcohols [3]

Oxidation of Alcohol


Mechanism In Humans

Note: The mechanism in yeast and bacteria is the reverse of this reaction.


  1. Binding of the coenzyme NAD+;
  2. Binding of the alcohol substrate by coordination

to zinc;

  1. Deprotonation of the His-51
  2. Deprotonation of nicotinamide ribose
  3. Deprotonation of Ser-48
  4. Deprotonation of the alcohol
  5. Hydride transfer from the alkoxide ion

to NAD+, leading to NADH and a zinc bound aldehyde or ketone;

  1. Release of the product aldehyde;

These steps are supported through kinetic studies.[4]


This is an example of the mechanism of liver alcohol dehydrogenase. 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. [5]

Active Site

This is the active site of alcohol dehydrogenase. The active site consists of a zinc atom, His-67, Cys-174, Cys-46, Ser-48, His-51, Ile-269, Val-292, Ala-317, and Phe-319. The zinc coordinates the substrate(alcohol). The zinc is coordinated by Cys-146, Cys-174, and His-67. Phe-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 from hydrogen bonds with the amide on NAD+[6].

In humans

In humans, it exists in multiple forms as a dimer and is encoded by at least seven different genes. There are four classes (I-IV) of alcohol dehydrogenase, but the hepatic form that is primarily used in humans is class 1. Class 1 consits of A,B, and C subunits that are encoded by the genes ADH1A, ADH1B, and ADH1C[7] The enzyme is contained in the lining of the stomach and in the liver. It catalyzes the oxidation of ethanol to acetaldehyde:


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. Others believe that its evolutionary purpose is involved in vitamin A metabolism, as alcohols are relatively 'empty' calories, providing no nutritional benefit.

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. All of them are dimers (consist 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.

In yeast and bacteria

Unlike humans, yeast and bacteria do not ferment glucose to lactate. Instead, they ferment it to ethanol and CO2. The overall reaction can be seen below.

Glucose + 2ADP +2Pi --> 2 ethanol + 2CO2 + 2ATP +2H2O [8]

In yeast 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. It is interesting to note that 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 only expressed 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.[1]

Iron-containing alcohol dehydrogenases

A third family of alcohol dehydrogenases, unrelated to the above two, are iron-containing ones. They occur in bacteria, and an (apparently inactive) form has also been found in yeast. In comparison to enzymes the above families, these enzymes are oxygen-sensitive.

Other alcohol dehydrogenase 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.


In fuel cells: Alcohol dehydrogenases can be used to catalyze the breakdown of fuel for an ethanol fuel cell. Scientists at Saint Louis University used carbon-supported alcohol dehydrogenase with poly(methylene green) as an anode, with a nafion membrane, to achieve about 50 μA/cm² [2].

In biotransformation: Alcohol dehydrogenases are often used for the synthesis of enantiomerically pure stereoisomers of chiral alcohols. In contrast to the chemical process, the enzymes yield directly the desired enatiomer of the alcohol by reduction of the corresponding ketone.

Health Issues


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 the risk of alcoholism. The studies have found that mutations of ADH2 and ADH3 are related to alcoholism in Asian populations. However, research continues in order to identify the genes and their influence on alcoholism.[9]

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[10].

See also


  1. ^ Sofer, W. and Martin, F. Presley. Annual Reviews. Analysis of Alcohol Dehydrogenase Gene Expression in Drosophila. 21 (1987):203-25.
  2. ^ Hammes-Schiffer, Sharon and Benkoviv, Stephen J. Relating Protein Motion to Catalysis. Annual Review of Biochemistry. 75(2006):519-41.
  3. ^ Sofer, W. and Martin, F. Presley. Annual Reviews. Analysis of Alcohol Dehydrogenase Gene Expression in Drosophila. 21 (1987):203-25.
  4. ^ Hammes-Schiffer, Sharon and Benkoviv, Stephen J. Relating Protein Motion to Catalysis. Annual Review of Biochemistry. 75(2006):519-41.
  5. ^ Hammes-Schiffer, Sharon and Benkovic, Stephen J. Relating Protein Motion to Catalysis. Annual Review of Biochemistry. 75(2006):519-41.
  6. ^ Hammes-Schiffer, Sharon and Benkoviv, Stephen J. Relating Protein Motion to Catalysis. Annual Review of Biochemistry. 75(2006):519-41
  7. ^ Sultatos and et. Toxicological Sciences. Incorporation of the Genetic control of Alcohol Dehydrogenase into a Physiologically Based Pharmacokinetic Model for Ethanol in Humans
  8. ^ Nelson, David L. and Cox, Michael M. Lehniger Principles of Biochemistry. New York:W.H. Freeman and Company, 2005; p 180.
  9. ^ Sher, Kenneth J., Grekin, Emily R., and Williams, Natalie A. The Development of Alcohol Use Disorders. Annual Review Clinical Psych. 1 (2005):493-523.
  10. ^ Luo and et. Oxford Journals. Multiple ADH genes modulate risk for drug dependence in African- and European-Americans
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  • EGO entry for GO code 0004022: alcohol dehydrogenase
  • AMIGO entry for GO code 0004022: alcohol dehydrogenase
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "Alcohol_dehydrogenase". A list of authors is available in Wikipedia.
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