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Gene Review

ALDH4A1  -  aldehyde dehydrogenase 4 family, member A1

Homo sapiens

Synonyms: ALDH4, Aldehyde dehydrogenase family 4 member A1, Delta-1-pyrroline-5-carboxylate dehydrogenase, mitochondrial, L-glutamate gamma-semialdehyde dehydrogenase, P5C dehydrogenase, ...
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Disease relevance of ALDH4A1

  • The conceptual translation of human P5CDh has 89% sequence identity with the published human P5CDh peptide sequences and 42 and 26% identity with Saccharomyces cerevisiae and Escherichia coli P5CDhs, respectively, as well as homology to several other aldehyde dehydrogenases [1].
  • We have confirmed the P5CDh activity of the Thermus thermophilus protein TT0033 (TtP5CDh), and determined the crystal structure of the enzyme in the ligand-free form at 1.4 A resolution [2].
  • Our research could be a further understanding of the biological significance of this P5CDh-ANF enzyme, with important potential applications in the treatment of HPII and liver diseases and in liver transplantation [3].

High impact information on ALDH4A1

  • To test the functional consequences of three of these, we expressed them in a P5CDh-deficient strain of Saccharomyces cerevisiae . In contrast to wild-type human P5CDh, yeast expressing S352L and G521fs(+1) failed to grow on proline and had no detectable P5CDh activity [4].
  • As an initial step in understanding the biochemistry of human P5CDh and molecular basis of HPII, we utilized published peptide sequence data and degenerate primer polymerase chain reaction to clone two full-length human P5CDh cDNAs, differing in length by 1 kilobase pair (kb) [1].
  • The P5CDh structural gene appears to be single copy with a size of about 20 kb localized to chromosome 1 [1].
  • In this paper we report an 800-fold purification P5C dehydrogenase from rat liver mitochondria to yield an essentially homogenous protein [5].
  • The fis1 gene has 73% homology with an Arabidopsis gene which encodes delta-1-pyrroline-5-carboxylate dehydrogenase (P5CDH) which is a part of the proline degradation pathway [6].

Biological context of ALDH4A1

  • These results suggest that p53 might play a protective role against cell damage induced by generation of intracellular ROS, through transcriptional activation of ALDH4 [7].
  • Inhibition of ALDH4 expression by antisense oligonucleotides was able to enhance cell death induced by infection with Ad-p53 [7].
  • Expression of ALDH4 mRNA was induced in HCT116 cells in response to DNA damage caused by adriamycin treatment, in a p53-dependent manner [7].
  • The activity of P5C metabolizing enzymes: OAT, P5CR, PO, and P5CD, in the camel tick Hyalomma dromedarii has been followed throughout embryogenesis [8].

Associations of ALDH4A1 with chemical compounds

  • Human liver high Km aldehyde dehydrogenase (ALDH4): properties and structural relationship to the glutamic gamma-semialdehyde dehydrogenase [9].
  • Cr(III) at 32 mg/L altered the expression of five genes, including GSTtau, GSTalpha, and ALDH4 [10].

Other interactions of ALDH4A1


Analytical, diagnostic and therapeutic context of ALDH4A1

  • Both P5CDh cDNA clones detect a single 3.2-kb transcript on Northern blots of multiple human tissues, indicating the long cDNA containing the 3'-untranslated intron represents the predominant transcript [1].
  • H1299 cells transformed to over-express ALDH4 showed significantly lower intracellular reactive oxygen species (ROS) levels than parental or control cells after treatment with hydrogen peroxide or UV [7].


  1. Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase. Hu, C.A., Lin, W.W., Valle, D. J. Biol. Chem. (1996) [Pubmed]
  2. Crystal Structure of Thermus thermophilus Delta(1)-Pyrroline-5-carboxylate Dehydrogenase. Inagaki, E., Ohshima, N., Takahashi, H., Kuroishi, C., Yokoyama, S., Tahirov, T. J. Mol. Biol. (2006) [Pubmed]
  3. Is rat LRRP Ba1-651 a Delta-1-pyrroline-5-carboxylate dehydrogenase activated by changes in the concentration of sweet molecules? Tizzano, M., Sbarbati, A. Med. Hypotheses (2007) [Pubmed]
  4. Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Geraghty, M.T., Vaughn, D., Nicholson, A.J., Lin, W.W., Jimenez-Sanchez, G., Obie, C., Flynn, M.P., Valle, D., Hu, C.A. Hum. Mol. Genet. (1998) [Pubmed]
  5. Pyrroline 5-carboxylate dehydrogenase of the mitochondrial matrix of rat liver. Purification, physical and kinetic characteristics. Small, W.C., Jones, M.E. J. Biol. Chem. (1990) [Pubmed]
  6. A rust-inducible gene from flax (fis1) is involved in proline catabolism. Mitchell, H.J., Ayliffe, M.A., Rashid, K.Y., Pryor, A.J. Planta (2006) [Pubmed]
  7. Identification of ALDH4 as a p53-inducible gene and its protective role in cellular stresses. Yoon, K.A., Nakamura, Y., Arakawa, H. J. Hum. Genet. (2004) [Pubmed]
  8. Enzymes of delta 1-pyrroline-5-carboxylate metabolism in the camel tick Hyalomma dromedarii during embryogenesis. Purification and characterization of delta 1-pyrroline-5-carboxylate dehydrogenases. Fahmy, A.S., Mohamed, S.A., Girgis, R.B., Abdel-Ghaffar, F.A. Comp. Biochem. Physiol. B, Biochem. Mol. Biol. (1997) [Pubmed]
  9. Human liver high Km aldehyde dehydrogenase (ALDH4): properties and structural relationship to the glutamic gamma-semialdehyde dehydrogenase. Agarwal, D.P., Eckey, R., Hempel, J., Goedde, H.W. Adv. Exp. Med. Biol. (1993) [Pubmed]
  10. Alterations in hepatic gene expression by trivalent chromium in Fundulus heteroclitus. Roling, J.A., Baldwin, W.S. Mar. Environ. Res. (2006) [Pubmed]
  11. Transitions in replication timing in a 340 kb region of human chromosomal R-Band 1p36.1. Brylawski, B.P., Cohen, S.M., Horne, H., Irani, N., Cordeiro-Stone, M., Kaufman, D.G. J. Cell. Biochem. (2004) [Pubmed]
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