Aldo-keto reductase family 1, member A1

Structure

Gene

The AKR1A1 gene lies on the chromosome location of 1p34.1 and consists of 10 exons.

Protein

AKR1A1 consists of 325 amino acids and weighs 36573Da. The tertiary structure consists of a beta/alpha-barrel, with the coenzyme-binding site located at the carboxy-terminus end of the strands of the barrel. Alternative splicing of this gene results in two transcript variants encoding the same protein.

Function

AKR1A1 gene is found highly expressed in kidney and liver, and moderately expressed in cerebrum, small intestine and testis. Small amounts of AKR1A1 are present in lung, prostate and spleen. However, it is not observed in heart or skeletal muscle. AKR1A1 belongs to the AKR superfamily, which are predominantly monomeric, soluble, NADPH-dependent oxidoreductases involved in the reduction of aldehydes and ketones into primary and secondary alcohols. AKR1A1 is shown to demonstrate characteristically high specific activity towards many aromatic and aliphatic aldehydes, and preferentially catalyses the NADPH-dependent reduction of aliphatic aldehydes, aromatic aldehydes and biogenic amines. It is also reported to be involved in the metabolism of 4-hydroxynonenal and play a role in the resistance to oxidative stress.

Clinical significance

A SNP in intron 5 of AKR1A1 has been found to be significantly associated with increased risk of non-Hodgkin's lymphoma. AKR1A1 could activate procarcinogens, such as polycyclic aromatic hydrocarbon. AKRs have been linked to metabolism of the anthracyclines doxorubicin (DOX) and daunorubicin (DAUN), allelic variants showed significantly reduced metabolic activities, and hence these allelic variants can possibly act as genetic biomarkers for the clinical development of DAUN-induced cardiotoxicity.

Interactions

4-hydroxynonenal

polycyclic aromatic hydrocarbon

DAUN

References

References

1. (June 1989). "The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases". The Journal of Biological Chemistry.
2. (Jul 1999). "The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33→p32". Cytogenetics and Cell Genetics.
3. "Entrez Gene: AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase)".
4. (January 2001). "Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1)". Chemico-Biological Interactions.
5. (April 2007). "Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma". Human Genetics.
6. (November 1994). "Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications". Acta Crystallographica Section D.
7. (August 2007). "Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms". Archives of Biochemistry and Biophysics.
8. (May 1995). "Catalysis of reduction of carbohydrate 2-oxoaldehydes (osones) by mammalian aldose reductase and aldehyde reductase". Biochimica et Biophysica Acta (BBA) - General Subjects.
9. (December 1991). "Expression of human aldose and aldehyde reductases. Site-directed mutagenesis of a critical lysine 262". The Journal of Biological Chemistry.
10. (September 1982). "Purification and properties of human liver aldehyde reductases". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology.
11. (March 2013). "[Effect of AKR1A1 knock-down on H2;O2; and 4-hydroxynonenal-induced cytotoxicity in human 1321N1 astrocytoma cells]". Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology.
12. (May 2008). "Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin". Drug Metabolism and Disposition.