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Gene Review

ALDH9A1  -  aldehyde dehydrogenase 9 family, member A1

Homo sapiens

Synonyms: 4-trimethylaminobutyraldehyde dehydrogenase, ALDH4, ALDH7, ALDH9, Aldehyde dehydrogenase E3 isozyme, ...
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Disease relevance of ALDH9A1


Psychiatry related information on ALDH9A1


High impact information on ALDH9A1

  • In the sheep blowfly, Lucilia cuprina, the association is due to a change in a specific esterase isozyme, E3, which, in resistant flies, has a null phenotype on gels stained using standard carboxylesterase substrates [6].
  • Restrictive-fragment-length polymorphisms have been identified with E3, which will permit further localization of this gene by genetic linkage analysis [7].
  • Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity [1].
  • Activation of separase occurs at anaphase onset, when securin is targeted for destruction by the anaphase-promoting complex or cyclosome E3 ubiquitin protein ligase [8].
  • These results indicate that His-452, which is a possible proton acceptor/donor in human E3 reaction, is critical to human E3 catalysis and that the local environment around His-452 and Glu-457, which are suggested to be hydrogen-bonded, is important in the binding of dihydrolipoamide to the enzyme [9].

Chemical compound and disease context of ALDH9A1


Biological context of ALDH9A1

  • Tryptic peptides derived from the purified brain protein matched the amino acid sequence of the liver E3 isoenzyme [12].
  • Employing liver E3 cDNA, a human cerebellar cDNA library was screened and a 2.0 kb cDNA fragment was isolated [12].
  • The full-length human kidney cDNA (ALDH7) is 2791 bp in length and contains an open reading frame encoding 468 amino acids (aa) [13].
  • Using a panel of human/hamster somatic cell hybrids we have localized, the gene coding for the E3 isozyme to human chromosome 1 [14].
  • Human liver aldehyde dehydrogenase (E3 isozyme), with wide substrate specificity and low Km for 4-aminobutyraldehyde, was only recently characterized [Kurys, G., Ambroziak, W. & Pietruszko, R. (1989) J. Biol. Chem. 264, 4715-4721] and in this study we report on its primary structure [15].

Anatomical context of ALDH9A1

  • The distribution of this enzyme in brain was investigated by Northern blot analysis, which demonstrated the presence of E3' mRNA in all regions of the human brain. mRNA levels were variable in the different brain areas, with the highest levels in the spinal cord and the lowest in the occipital pole [12].
  • The highest levels of the E3 isozyme activity were found in liver, adrenal gland, and kidney [16].
  • Northern blot analysis, however, differed from that of enzyme assay and the Western blot in that it showed highest mRNA levels in skeletal and heart muscles, which had low enzyme activities and E3 protein levels [16].
  • Interestingly, additional deletion of the E4 gene obviated the upregulation of genes in endothelial cells by the E1(-) E3(-) Ad vector, suggesting that genes carried by the E4 region play a central role in modifying target cell gene expression [17].
  • We have described an Ad nuclear membrane glycoprotein of 11,600 kDa (E3-11.6K) which is encoded by the E3 transcription unit and which is synthesized in small amounts from the E3 promoter at early stages of infection but in large amounts from the major late promoter at very late stages of infection [18].

Associations of ALDH9A1 with chemical compounds

  • It had the physico-chemical and kinetic properties of the human liver E3 isoenzyme of aldehyde dehydrogenase (EC, and also interacted with an anti-(liver E3 isoenzyme) antibody [12].
  • The cerebellar cDNA yielded a derived primary structure which differed from the liver E3 amino acid sequence by a single serine-to-cysteine substitution at position 88 (position 84 in the liver sequence) [12].
  • ALDH-4, ALDH-5 and betaine aldehyde dehydrogenase did not catalyze the oxidation of either aldophosphamide or retinaldehyde [19].
  • The cDNA and the gene (ALDH9) for a human aldehyde dehydrogenase isozyme, which has a high activity for oxidation of gamma-aminobutyraldehyde and other amino aldehydes, were cloned and characterized [20].
  • This distribution is consistent with the possible physiological role of E3 isozyme in the synthesis of the osmolyte, betaine, and the neurotransmitter, GABA [16].

Other interactions of ALDH9A1

  • The human ALDH8 gene was identified during the process of the screening for the human ALDH7 genomic clones [21].
  • This longest putative open reading frame (ORF) encodes a polypeptide chain of 385 aa residues, includes the two ALDH conserved regions, and demonstrates 86% identity with the corresponding ORF region of the human ALDH7 [21].
  • The NDUFS8 gene is located on chromosome 11q13 immediately downstream of the ALDH7 isoform gene [22].

Analytical, diagnostic and therapeutic context of ALDH9A1

  • These same tissues also showed highest levels of the E3 protein via the Western blot [16].
  • To examine the importance of this highly conserved Ile-51 in human E3 function, it was substituted with Ala using site-directed mutagenesis [23].
  • E3 was isolated from the inhibited PD complex and CNBr cleavage of the inhibited enzyme yielded a single radiolabelled peptide that was purified on a cyanopropyl silica column using high performance liquid chromatography [24].
  • Sequence analysis indicated that the meningococcal E2p (Men-E2p) contains two N-terminal lipoyl domains, an E1/E3 binding domain and a catalytic domain [25].


  1. Biochemical analysis of Parkinson's disease-causing variants of Parkin, an E3 ubiquitin-protein ligase with monoubiquitylation capacity. Hampe, C., Ardila-Osorio, H., Fournier, M., Brice, A., Corti, O. Hum. Mol. Genet. (2006) [Pubmed]
  2. Expression of cDNA sequences encoding mature and precursor forms of human dihydrolipoamide dehydrogenase in Escherichia coli. Differences in kinetic mechanisms. Kim, H., Liu, T.C., Patel, M.S. J. Biol. Chem. (1991) [Pubmed]
  3. Studies of urinary organic acid profiles of a patient with dihydrolipoyl dehydrogenase deficiency. Kuhara, T., Shinka, T., Inoue, Y., Matsumoto, M., Yoshino, M., Sakaguchi, Y., Matsumoto, I. Clin. Chim. Acta (1983) [Pubmed]
  4. Leigh disease with deficiency of lipoamide dehydrogenase: treatment failure with dichloroacetate. Craigen, W.J. Pediatric neurology. (1996) [Pubmed]
  5. Leigh syndrome due to compound heterozygosity of dihydrolipoamide dehydrogenase gene mutations. Description of the first E3 splice site mutation. Grafakou, O., Oexle, K., van den Heuvel, L., Smeets, R., Trijbels, F., Goebel, H.H., Bosshard, N., Superti-Furga, A., Steinmann, B., Smeitink, J. Eur. J. Pediatr. (2003) [Pubmed]
  6. A single amino acid substitution converts a carboxylesterase to an organophosphorus hydrolase and confers insecticide resistance on a blowfly. Newcomb, R.D., Campbell, P.M., Ollis, D.L., Cheah, E., Russell, R.J., Oakeshott, J.G. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  7. Three genes for enzymes of the pyruvate dehydrogenase complex map to human chromosomes 3, 7, and X. Olson, S., Song, B.J., Huh, T.L., Chi, Y.T., Veech, R.L., McBride, O.W. Am. J. Hum. Genet. (1990) [Pubmed]
  8. Protein phosphatase 2A stabilizes human securin, whose phosphorylated forms are degraded via the SCF ubiquitin ligase. Gil-Bernabé, A.M., Romero, F., Limón-Mortés, M.C., Tortolero, M. Mol. Cell. Biol. (2006) [Pubmed]
  9. Characterization of two site-specifically mutated human dihydrolipoamide dehydrogenases (His-452----Gln and Glu-457----Gln). Kim, H., Patel, M.S. J. Biol. Chem. (1992) [Pubmed]
  10. The pyruvate dehydrogenase multi-enzyme complex from Gram-negative bacteria. de Kok, A., Hengeveld, A.F., Martin, A., Westphal, A.H. Biochim. Biophys. Acta (1998) [Pubmed]
  11. Enzymatic method for branched chain alpha-ketoacid determination: application to rapid analysis of urine and plasma samples from maple syrup urine disease patients. Burgos, C., Civallero, G.E., de Kremer, R.D., Gerez de Burgos, N.M., Blanco, A. Acta physiologica, pharmacologica et therapeutica latinoamericana : órgano de la Asociación Latinoamericana de Ciencias Fisiológicas y [de] la Asociación Latinoamericana de Farmacología. (1999) [Pubmed]
  12. Aldehyde dehydrogenase from adult human brain that dehydrogenates gamma-aminobutyraldehyde: purification, characterization, cloning and distribution. Kikonyogo, A., Pietruszko, R. Biochem. J. (1996) [Pubmed]
  13. Cloning of a cDNA encoding human ALDH7, a new member of the aldehyde dehydrogenase family. Hsu, L.C., Chang, W.C., Yoshida, A. Gene (1994) [Pubmed]
  14. Human aldehyde dehydrogenase: chromosomal assignment of the gene for the isozyme that metabolizes gamma-aminobutyraldehyde. McPherson, J.D., Wasmuth, J.J., Kurys, G., Pietruszko, R. Hum. Genet. (1994) [Pubmed]
  15. Human aldehyde dehydrogenase. cDNA cloning and primary structure of the enzyme that catalyzes dehydrogenation of 4-aminobutyraldehyde. Kurys, G., Shah, P.C., Kikonygo, A., Reed, D., Ambroziak, W., Pietruszko, R. Eur. J. Biochem. (1993) [Pubmed]
  16. Tissue distribution of human aldehyde dehydrogenase E3 (ALDH9): comparison of enzyme activity with E3 protein and mRNA distribution. Izaguirre, G., Kikonyogo, A., Pietruszko, R. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (1997) [Pubmed]
  17. Induction of endogenous genes following infection of human endothelial cells with an E1(-) E4(+) adenovirus gene transfer vector. Ramalingam, R., Rafii, S., Worgall, S., Hackett, N.R., Crystal, R.G. J. Virol. (1999) [Pubmed]
  18. The adenovirus death protein (E3-11.6K) is required at very late stages of infection for efficient cell lysis and release of adenovirus from infected cells. Tollefson, A.E., Scaria, A., Hermiston, T.W., Ryerse, J.S., Wold, L.J., Wold, W.S. J. Virol. (1996) [Pubmed]
  19. Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde. Dockham, P.A., Lee, M.O., Sladek, N.E. Biochem. Pharmacol. (1992) [Pubmed]
  20. Human gamma-aminobutyraldehyde dehydrogenase (ALDH9): cDNA sequence, genomic organization, polymorphism, chromosomal localization, and tissue expression. Lin, S.W., Chen, J.C., Hsu, L.C., Hsieh, C.L., Yoshida, A. Genomics (1996) [Pubmed]
  21. Sequencing and expression of the human ALDH8 encoding a new member of the aldehyde dehydrogenase family. Hsu, L.C., Chang, W.C. Gene (1996) [Pubmed]
  22. Genomic structure of the human NDUFS8 gene coding for the iron-sulfur TYKY subunit of the mitochondrial NADH:ubiquinone oxidoreductase. de Sury, R., Martinez, P., Procaccio, V., Lunardi, J., Issartel, J.P. Gene (1998) [Pubmed]
  23. Activity of human dihydrolipoamide dehydrogenase is largely reduced by mutation at isoleucine-51 to alanine. Kim, H. J. Biochem. Mol. Biol. (2006) [Pubmed]
  24. The amino acid sequence encompassing the active-site histidine residue of lipoamide dehydrogenase from Escherichia coli labelled with a bifunctional arsenoxide. Holmes, C.F., Stevenson, K.J. Biochem. Cell Biol. (1986) [Pubmed]
  25. Cloning, sequencing, characterisation and implications for vaccine design of the novel dihydrolipoyl acetyltransferase of Neisseria meningitidis. Ala' Aldeen, D.A., Westphal, A.H., De Kok, A., Weston, V., Atta, M.S., Baldwin, T.J., Bartley, J., Borriello, S.P. J. Med. Microbiol. (1996) [Pubmed]
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