Alternative titles; symbols
HGNC Approved Gene Symbol: ALDH1A1
Cytogenetic location: 9q21.13 Genomic coordinates (GRCh38): 9:72,900,671-72,953,053 (from NCBI)
The ALDH1A1 gene encodes a liver cytosolic isoform of acetaldehyde dehydrogenase (EC 1.2.1.3), an enzyme involved in the major pathway of alcohol metabolism after alcohol dehydrogenase (ADH, see 103700). See also liver mitochondrial ALDH2 (100650), variation in which has been implicated in different responses to alcohol ingestion.
ALDH1 is associated with a low Km for NAD, a high Km for acetaldehyde, and is strongly inactivated by disulfiram. ALDH2 is associated with a high Km for NAD, and low Km for acetaldehyde, and is insensitive to inhibition by disulfiram (Hsu et al., 1985).
Inoue et al. (1979) purified and partially characterized aldehyde dehydrogenase from human erythrocytes: this was the cytosolic form, present in only low concentration in red cells. Using isoelectric focusing, Thomas et al. (1982) showed that the cytosolic and mitochondrial ALDHs are distinct isozymes. Hempel et al. (1984) determined the amino acid sequence of the cytosolic ALDH isoform. The monomer is composed of 500 residues and contains 11 cysteine residues.
Hsu et al. (1985) reported cloning of the ALDH1 and ALDH2 genes. The 2 proteins showed 69% homology at the protein level. The ALDH1 gene encodes a 501-residue protein (Hsu et al., 1989).
With cDNA probes for Southern blot analysis of somatic cell hybrids, Hsu et al. (1985, 1986) assigned the ALDH1 locus to chromosome 9q and the ALDH2 locus to chromosome 12.
Hsu et al. (1989) found that the ALDH1 gene is about 53 kb long and is divided into 13 exons. A similar intron-exon organization was found in ALDH2, which also has 13 exons with 9 of the 12 introns interrupting the coding sequence at positions homologous to those in ALDH1. Thus, the 2 isozymes appear to have evolved after duplication of a common ancestral gene.
Kim et al. (2015) showed that GABA corelease in midbrain dopamine neurons is mediated by ALDH1a1, the most abundant form of aldehyde dehydrogenase, in an evolutionarily conserved GABA synthesis pathway. GABA corelease is modulated by ethanol at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. Kim et al. (2015) concluded that their findings provided insights into the functional role of GABA corelease in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction.
Thomas et al. (1982) found low cytosolic ALDH in the liver of alcoholic patients with fatty liver; mitochondrial ALDH was normal. Abstaining alcoholics showed persistently low cytosolic ALDH.
Eckey et al. (1986) reported a variant of cytosolic ALDH in a Chinese autopsy liver specimen. While the major isozyme band was nearly absent, several additional minor bands were observed on isoelectric focusing gel. Rabbit antibodies showed immunological cross-reactivity for the variant enzyme bands. The existence of additional minor bands indicated the presence of tetramer hybrid forms made up of normal and variant monomers. The observed abnormality may represent a heterozygous form of cytosolic ALDH variation. A similar variant was also detected in erythrocytes of a male Thai student.
Yoshida et al. (1989) demonstrated that among Caucasians alcohol flushing can be related to abnormalities of ALDH1. In 9 unrelated Caucasian alcohol flushers, they found 1 who exhibited low activity (10-20% of normal) and another who exhibited moderately low activity (60%) and altered kinetic properties. The electrophoretic mobilities of these 2 samples were not altered. Immunologic quantitation indicated that the amount of protein in the 2 samples was not reduced in parallel with the enzyme deficiency. In the first case, the daughter of the proposita also had very low enzyme activity and alcohol flushing.
Retinaldehyde is generated by ADH1 (103700) from retinol, and its concentration is determined in large part by its subsequent catabolism by RALDH1 to retinoic acid. Ziouzenkova et al. (2007) demonstrated that retinaldehyde is present in rodent fat, binds retinol-binding proteins (CRBP1, 180260; RBP4, 180250), and suppresses PPARG (601487) and retinoid X receptor (see 180245) responses. Raldh1 -/- mice resisted diet-induced obesity and insulin resistance and showed increased energy dissipation. In ob/ob (see 164160) mice, administering retinaldehyde or a Raldh inhibitor reduced fat and increased insulin sensitivity. Ziouzenkova et al. (2007) concluded that retinaldehyde is a distinct transcriptional regulator of the metabolic responses to a high-fat diet.
Eckey, R., Agarwal, D. P., Saha, N., Goedde, H. W. Detection and partial characterization of a variant form of cytosolic aldehyde dehydrogenase isozyme. Hum. Genet. 72: 95-97, 1986. [PubMed: 3943866] [Full Text: https://doi.org/10.1007/BF00278826]
Hempel, J., von Bahr-Lindstrom, H., Jornvall, H. Aldehyde dehydrogenase from human liver: primary structure of the cytoplasmic isoenzyme. Europ. J. Biochem. 141: 21-35, 1984. [PubMed: 6723659] [Full Text: https://doi.org/10.1111/j.1432-1033.1984.tb08150.x]
Hsu, L. C., Chang, W.-C., Yoshida, A. Genomic structure of the human cytosolic aldehyde dehydrogenase gene. Genomics 5: 857-865, 1989. [PubMed: 2591967] [Full Text: https://doi.org/10.1016/0888-7543(89)90127-4]
Hsu, L. C., Tani, K., Fujiyoshi, T., Kurachi, K., Yoshida, A. Cloning of cDNAs for human aldehyde dehydrogenases 1 and 2. Proc. Nat. Acad. Sci. 82: 3771-3775, 1985. [PubMed: 2987944] [Full Text: https://doi.org/10.1073/pnas.82.11.3771]
Hsu, L. C., Yoshida, A., Mohandas, T. Chromosomal assignment of the genes for human aldehyde dehydrogenase-1 and aldehyde dehydrogenase-2. Am. J. Hum. Genet. 38: 641-648, 1986. [PubMed: 3013004]
Inoue, K., Nishimukai, H., Yamasawa, K. Purification and partial characterization of aldehyde dehydrogenase from human erythrocytes. Biochim. Biophys. Acta 569: 117-123, 1979. [PubMed: 224930] [Full Text: https://doi.org/10.1016/0005-2744(79)90046-9]
Kim, J.-I., Ganesan, S., Luo, S. X., Wu, Y.-W., Park, E., Huang, E. J., Chen, L., Ding, J. B. Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons. Science 350: 102-106, 2015. [PubMed: 26430123] [Full Text: https://doi.org/10.1126/science.aac4690]
Thomas, M., Halsall, S., Peters, T. J. Role of hepatic acetaldehyde dehydrogenase in alcoholism: demonstration of persistent reduction of cytosolic activity in abstaining patients. Lancet 320: 1057-1059, 1982. Note: Originally Volume II. [PubMed: 6127541] [Full Text: https://doi.org/10.1016/s0140-6736(82)90001-0]
Yoshida, A., Dave, V., Ward, R. J., Peters, T. J. Cytosolic aldehyde dehydrogenase (ALDH1) variants found in alcohol flushers. Ann. Hum. Genet. 53: 1-7, 1989. [PubMed: 2729894] [Full Text: https://doi.org/10.1111/j.1469-1809.1989.tb01116.x]
Ziouzenkova, O., Orasanu, G., Sharlach, M., Akiyama, T. E., Berger, J. P., Viereck, J., Hamilton, J. A., Tang, G., Dolnikowski, G. G., Vogel, S., Duester, G., Plutzky, J. Retinaldehyde represses adipogenesis and diet-induced obesity. Nature Med. 13: 695-702, 2007. [PubMed: 17529981] [Full Text: https://doi.org/10.1038/nm1587]