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Aldehyde dehydrogenase

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Chimera Image of a Monomer of Aldehyde Dehydrogenase 2 with a space filling model of NAD+ in the active site. (ALDH2, pdb code: 1o02)

Aldehyde dehydrogenases (EC 1.2.1.3) are a group of enzymes that catalyse the oxidation (dehydrogenation) of aldehydes.

Mitochondrial Aldehyde Dehydrogenase is a polymorphic enzyme (Crabb 2004) responsible for the oxidation of aldehydes to carboxylic acids, which leave the liver and are metabolized by the body’s muscle and heart (Crabb 2004). There are three different classes of these enzymes in mammals: class 1 (low Km, cytosolic), class 2 (low Km, mitochondrial), and class 3 (high Km, such as those expressed in tumors, stomach and cornea). In all three classes constitutive and inducible forms exist. ALDH1 and ALDH2 are the most important enzymes for aldehyde oxidation, and both are tetrameric enzymes composed of 54kDA subunits. These enzymes are found in many tissues of the body, but are at the highest concentration in the liver (Crabb 2004).

Chimera Image of a Tetramer of Aldehyde Dehydrogenase 2 (4 subunits) with a space filling model of NAD+ in each active site. (ALDH2, pdb code: 1o02).

Enzyme Active Site

This figure depicts the active site of a human mitochondrial aldehyde dehydrogenase 2 (ALDH2, pdb code: 1o02). Cys302 and Glu268 interact with the aldehyde substrate. The NAD+ is held in place by multiple residues (shown as wires or sticks) in the active site. Glu399 and Lys192 playing particular importance in the interact with NAD+.

The active site of the aldehyde dehydrogenase enzyme is largely conserved throughout the different classes of the enzyme and, although the number of amino acids present in a subunit can change, the overall function of the site changes little. The active site will contain one molecule of an aldehyde and an NAD(P)+ that functions as a cofactor. A cysteine and a glutamate will interact with the aldehyde substrate. Many other residues will interact with the NAD(P)+ to hold it in place. A magnesium may be used to help the enzyme function, although the amount it helps the enzyme can vary between different classes of aldehydes.

Mechanism

The overall reaction catalysed by the aldehyde dehydrogenases is:

RCHO + NAD+ + H2O → RCOOH + NADH + H+

In this NAD(P)+ dependent reaction, the aldehyde enters the active site through a channel located on the outside of the enzyme. The active site contains a Rossman fold and interactions between the cofactor and the fold allow for the isomerization of the enzyme while keeping the active site functional (Liu 1997).

Mechanism of Aldehyde Dehydrogenase

A sulfur from a cysteine in the active site makes a nucleophilic attack on the carbonyl carbon of the aldehyde. The hydrogen is kicked off as a hydride and attacks NAD(P)+ to make NAD(P)H. The enzyme's active site then goes through an isomorphic change where the NAD(P)H is moved, creating room for a water molecule to access the substrate. The water is primed by a glutamate in the active site, and the water makes a nucleophilic attack on the carbonyl carbon, kicking off the sulfur as a leaving group.

Pathology

A Chimera Image of the active site of Aldehyde Dehydrogenase 2 with a space filling model of NAD+ in the active site. Highlights the amino acid Glu349, which is mutated to a lysine in the inactive form of the enzyme. (ALDH2, pdb code:2onp)

ALDH2 plays a crucial role in maintaining low blood levels of acetaldehyde during alcohol oxidation. In this pathway, the intermediate structures can be toxic, and health problems arise when those intermediates cannot be cleared (Crabb 2004). When high levels of acetaldehyde occur in the blood, symptoms of facial flushing, light headedness, palpitations, nausea, and general “hangover” symptoms occur . These symptoms are indicative of a disease known as “Asian Flush” or “Oriental Flushing Syndrome” (Thomasson 1991).

There is a mutant form of aldehyde dehydrogenase, termed ALDH2*2, where a lysine residue replaces a glutamate in the active site at position 487 of ALDH2 (Steinmetz 1997). Homozygous individuals with the mutant allele have almost no ALDH2 activity, and those who are heterozygous for the mutation have reduced activity. Thus, the mutation is partially dominant (Crabb 2004). The ineffective homozygous allele works at a rate of about 8% of the normal allele, for it shows a higher km for NAD+ and has a higher maximum velocity than the wild type allele (Crabb 2004). This mutation is common in Japan, where 41% of a non-alcoholic control group were ALDH2 deficient, where only 2-5% of an alcoholic group were ALDH2 deficient. In Taiwan, the numbers are similar, with 30% of the control group showing the deficiency and 6% of alcoholics displaying it (Crabb 2004). The deficiency is manifested by slow acetaldehyde removal, low alcohol tolerance perhaps which leads to a lower frequency of alcoholism (Thomasson 1991), (Crabb 2004).

These symptoms are the same as those observed in people who drink while being treated by the drug disulfiram, which is why it is used to treat alcoholism. The patients show higher blood levels of acetaldehyde, and become violently ill upon consumption of even small amounts of alcohol (Crabb 2004). Several drugs (e.g., metronidazole) cause a similar reaction known as "disulfiram-like reaction."

Yokoyama et al. found that decreased enzyme activity of aldehyde dehydrogenase-2, caused by the mutated ALDH2 allele, contributes to a higher chance of esophageal and oropharyngolaryngeal cancers. The metabolized acetaldehyde in the blood, which is six times higher than in individuals without the mutation, has shown to be a carcinogen in lab animals. However, they found no connection between increased levels of ALDH2*2 in the blood and an increased risk of liver cancer (Yokoyama 1998).

Genes

See also

References

  • Crabb DW, Matsumoto M, Chang D, You M (2004). "Overview of the role of alcohol dehydrogenase and aldehyde dehydrogenase and their variants in the genesis of alcohol-related pathology". The Proceedings of the Nutrition Society. 63 (1): 49–63. doi:10.1079/PNS2003327. PMID 15099407. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Liu ZJ, Sun YJ, Rose J; et al. (1997). "The first structure of an aldehyde dehydrogenase reveals novel interactions between NAD and the Rossmann fold". Nature Structural Biology. 4 (4): 317–26. doi:10.1038/nsb0497-317. PMID 9095201. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Steinmetz CG, Xie P, Weiner H, Hurley TD (1997). "Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion". Structure. 5 (5): 701–11. doi:10.1016/S0969-2126(97)00224-4. PMID 9195888. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Thomasson HR, Edenberg HJ, Crabb DW; et al. (1991). "Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men". American Journal of Human Genetics. 48 (4): 677–81. PMC 1682953. PMID 2014795. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  • Yokoyama A, Muramatsu T, Ohmori T; et al. (1998). "Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics". Carcinogenesis. 19 (8): 1383–7. doi:10.1093/carcin/19.8.1383. PMID 9744533. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)

Molecular graphics images were produced using the UCSF Chimera package from the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIH P41 RR-01081).

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