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Aldehyde dehydrogenase 2 family (mitochondrial)
Protein ALDH2 PDB 1a4z.png
PDB rendering based on 1a4z.
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM100650 MGI99600 HomoloGene55480 ChEMBL: 1935 GeneCards: ALDH2 Gene
EC number
RNA expression pattern
PBB GE ALDH2 201425 at tn.png
More reference expression data
Species Human Mouse
Entrez 217 11669
Ensembl ENSG00000111275 ENSMUSG00000029455
UniProt P05091 P47738
RefSeq (mRNA) NM_000690 NM_001308450
RefSeq (protein) NP_000681 NP_001295379
Location (UCSC) Chr 12:
111.77 – 111.82 Mb
Chr 5:
121.57 – 121.59 Mb
PubMed search [1] [2]

Aldehyde dehydrogenase 2 family (mitochondrial), also known as ALDH2, is a human gene found on chromosome 12.[1][2] This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer. This gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[3]


The ALDH2 gene is about 44 kbp in length and contains at least 13 exons which encode 517 amino acid residues. Except for the signal NH2-terminal peptide, which is absent in the mature enzyme, the amino acid sequence deduced from the exons coincided with the reported primary structure of human liver ALDH2. Several introns contain Alu repetitive sequences. A TATA-like sequence (TTATAAAA) and a CAAT-like sequence (GTCATCAT) are located 473 and 515 bp, respectively, upstream from the translation initiation codon.[4]

The enzyme encoded by the human ALDH2 gene is a tetrameric enzyme that contains three domains; two dinucleotide-binding domains and a three-stranded beta-sheet domain. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476.[5] Although there is a recognizable Rossmann fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.[6]


Two major liver isoforms of this enzyme, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. The ALDH2 gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix; in contrast the ALDH1 gene codes for the cytosolic isoform.[3]


The enzyme encoded by this gene belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Additionally, ALDH2 functions as a protector against oxidative stress.[7]

             &\text{H}&     &\text{H}&                          &                    &             &\text{H}&     &\text{H}&                      &             &\text{H}&     &        &                          \\
             &      | &     &      | &                          &\mathsf{ADH}        &             &      | &     &      | &\mathsf{ALDH}         &             &      | &     &        &                          \\
\text{H}\,-\!&\text{C}&\!-\!&\text{C}&\!-\,\text{O}\,-\,\text{H}&\xrightarrow{\qquad}&\text{H}\,-\!&\text{C}&\!-\!&\text{C}&\xrightarrow{\qquad\ }&\text{H}\,-\!&\text{C}&\!-\!&\text{C}&\!-\,\text{O}\,-\,\text{H}\\ 
             &      | &     &      | &                          &                    &             &      | &     &     \| &                      &             &      | &     &     \| &                          \\
             &\text{H}&     &\text{H}&                          &                    &             &\text{H}&     &\text{O}&                      &             &\text{H}&     &\text{O}&                          \\
Metabolism of alcohol (ethanol) to acetaldehyde (ethanal) and then acetic acid (ethanoic acid)

Clinical significance[edit]

Most Europeans have two major isozymes, while approximately 50% of Northeast Asians have one normal copy of the ALDH2 gene and one variant copy that encodes an inactive mitochondrial isoenzyme. In native Japanese, this variant ALDH2 gene encodes lysine instead of glutamic acid at amino acid 487 and therefore encodes a product protein that is completely inactive in metabolizing acetaldehyde to acetic acid.[8] In the overall Japanese population, about 57% of individuals are homozygous for the normal gene, 40% are heterozygous for the variant gene, and 3% are homozygous for the variant gene.[8] Since ALDH2 assembles and functions as a tetramer and requires all four of its components to be active in order to metabolize acetaldehyde, heterozygotes have very little ALDH2 activity.[9] Accordingly, Japanese individuals heterozygous or homozygous for the abnormal gene metabolize ethanol to acetaldehyde normally but metabolize acetaldehyde poorly and are thereby susceptible to certain adverse effects of alcoholic (i.e. ethanol-containing) beverages; these effects include the transient accumulation of acetaldehyde in blood and tissues; facial flushing (i.e. the "oriental flushing syndrome"), urticaria, systemic dermatitis, and alcohol-induced respiratory reactions such as rhinitis and the exacerbation of asthma bronchoconstriction.[10] The cited allergic reaction-like symptoms: a) do not appear due to classical IgE or T cell-related allergen-induced reactions but rather to the actions of acetaldehyde in stimulating the release of histamine, a probable mediating cause of these symptoms; b) typically occur within 30–60 minutes of ingesting alcoholic beverages; and c) occur in other Asian as well as non-Asian individuals that are either seriously defective in metabolizing ingested ethanol past acetaldehyde to acetic acid or, alternatively, that metabolize ethanol too rapidly for ALDH2 processing.[10][11]

A remarkably higher frequency of acute alcohol intoxication among Northeast Asians than among Europeans has been repeatedly shown to be related to the very much reduced activity of the variant ALDH2-2 isoenzyme.[3] During the 80's there has been a steady increase in the number of Japanese alcoholics who manage to overcome their genetically determined aversion to alcoholism from the dominant effects of an ALDH2-2 mutation.[12] This trend demonstrates that, even among those least likely to succumb to alcoholism, there are social pressures to drink.[12]

An activator of ALDH2 enzymatic activity, Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide), has been shown to reduce ischemia-induced cardiac damage caused by myocardial infarction.[13]


ALDH2 has been shown to interact with GroEL.[14]

See also[edit]


  1. ^ Yoshida A, Ikawa M, Hsu LC, Tani K (1985). "Molecular abnormality and cDNA cloning of human aldehyde dehydrogenases". Alcohol 2 (1): 103–6. doi:10.1016/0741-8329(85)90024-2. PMID 4015823. 
  2. ^ Hsu LC, Tani K, Fujiyoshi T, Kurachi K, Yoshida A (Jun 1985). "Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2". Proceedings of the National Academy of Sciences of the United States of America 82 (11): 3771–5. doi:10.1073/pnas.82.11.3771. PMC 397869. PMID 2987944. 
  3. ^ a b c "Entrez Gene: ALDH2 aldehyde dehydrogenase 2 family (mitochondrial)". 
  4. ^ Hsu LC, Bendel RE, Yoshida A (Jan 1988). "Genomic structure of the human mitochondrial aldehyde dehydrogenase gene". Genomics 2 (1): 57–65. PMID 2838413. 
  5. ^ González-Segura L, Ho KK, Perez-Miller S, Weiner H, Hurley TD (Feb 2013). "Catalytic contribution of threonine 244 in human ALDH2". Chemico-Biological Interactions 202 (1-3): 32–40. doi:10.1016/j.cbi.2012.12.009. PMID 23295226. 
  6. ^ Steinmetz CG, Xie P, Weiner H, Hurley TD (May 1997). "Structure of mitochondrial aldehyde dehydrogenase: the genetic component of ethanol aversion". Structure 5 (5): 701–11. PMID 9195888. 
  7. ^ Ohta S, Ohsawa I, Kamino K, Ando F, Shimokata H (Apr 2004). "Mitochondrial ALDH2 deficiency as an oxidative stress". Annals of the New York Academy of Sciences 1011: 36–44. PMID 15126281. 
  8. ^ a b Takao A, Shimoda T, Kohno S, Asai S, Harda S (May 1998). "Correlation between alcohol-induced asthma and acetaldehyde dehydrogenase-2 genotype". The Journal of Allergy and Clinical Immunology 101 (5): 576–80. doi:10.1016/S0091-6749(98)70162-9. PMID 9600491. 
  9. ^ Koppaka V, Thompson DC, Chen Y, Ellermann M, Nicolaou KC, Juvonen RO, Petersen D, Deitrich RA, Hurley TD, Vasiliou V (Jul 2012). "Aldehyde dehydrogenase inhibitors: a comprehensive review of the pharmacology, mechanism of action, substrate specificity, and clinical application". Pharmacological Reviews 64 (3): 520–39. doi:10.1124/pr.111.005538. PMID 22544865. 
  10. ^ a b Adams KE, Rans TS (Dec 2013). "Adverse reactions to alcohol and alcoholic beverages". Annals of Allergy, Asthma & Immunology 111 (6): 439–45. doi:10.1016/j.anai.2013.09.016. PMID 24267355. 
  11. ^ Linneberg A, Gonzalez-Quintela A, Vidal C, Jørgensen T, Fenger M, Hansen T, Pedersen O, Husemoen LL (Jan 2010). "Genetic determinants of both ethanol and acetaldehyde metabolism influence alcohol hypersensitivity and drinking behaviour among Scandinavians". Clinical and Experimental Allergy 40 (1): 123–30. doi:10.1111/j.1365-2222.2009.03398.x. PMID 20205700. 
  12. ^ a b Higuchi S, Matsushita S, Imazeki H, Kinoshita T, Takagi S, Kono H (Mar 1994). "Aldehyde dehydrogenase genotypes in Japanese alcoholics". Lancet 343 (8899): 741–2. doi:10.1016/S0140-6736(94)91629-2. PMID 7907720. 
  13. ^ Chen CH, Budas GR, Churchill EN, Disatnik MH, Hurley TD, Mochly-Rosen D (Sep 2008). "Activation of aldehyde dehydrogenase-2 reduces ischemic damage to the heart". Science 321 (5895): 1493–5. doi:10.1126/science.1158554. PMC 2741612. PMID 18787169. 
  14. ^ Lee KH, Kim HS, Jeong HS, Lee YS (Oct 2002). "Chaperonin GroESL mediates the protein folding of human liver mitochondrial aldehyde dehydrogenase in Escherichia coli". Biochemical and Biophysical Research Communications 298 (2): 216–24. doi:10.1016/S0006-291X(02)02423-3. PMID 12387818. 

Further reading[edit]

External links[edit]