Aldo-keto reductase family 1, member A1 explained

Alcohol dehydrogenase [NADP+] also known as aldehyde reductase or aldo-keto reductase family 1 member A1 is an enzyme that in humans is encoded by the AKR1A1 gene.^{[1] [2] [3]} AKR1A1 belongs to the aldo-keto reductase (AKR) superfamily. It catalyzes the NADPH-dependent reduction of a variety of aromatic and aliphatic aldehydes to their corresponding alcohols and catalyzes the reduction of mevaldate to mevalonic acid and of glyceraldehyde to glycerol.^[4] Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.^[5]

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.^[6] 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.^[7] 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.^[8] 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.^{[9] [10] [11]} It is also reported to be involved in the metabolism of 4-hydroxynonenal and play a role in the resistance to oxidative stress.^[12]

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.^[13]

Interactions

4-hydroxynonenal

polycyclic aromatic hydrocarbon

DAUN

Further reading

• Dawson SJ, White LA . Treatment of Haemophilus aphrophilus endocarditis with ciprofloxacin . The Journal of Infection . 24 . 3 . 317–20 . May 1992 . 1602151 . 10.1016/S0163-4453(05)80037-4 .
• Tanimoto T, Ohta M, Tanaka A, Ikemoto I, Machida T . Purification and characterization of human testis aldose and aldehyde reductase . The International Journal of Biochemistry . 23 . 4 . 421–8 . 1991 . 1901806 . 10.1016/0020-711X(91)90169-N .
• Vander Jagt DL, Hunsaker LA, Robinson B, Stangebye LA, Deck LM . Aldehyde and aldose reductases from human placenta. Heterogeneous expression of multiple enzyme forms . The Journal of Biological Chemistry . 265 . 19 . 10912–8 . July 1990 . 10.1016/S0021-9258(19)38533-3 . 2113526 . free .
• Wermuth B, Omar A, Forster A, di Francesco C, Wolf M, von Wartburg JP, Bullock B, Gabbay KH . Primary structure of aldehyde reductase from human liver . Progress in Clinical and Biological Research . 232 . 297–307 . 1987 . 3615425 .
• Barski OA, Gabbay KH, Grimshaw CE, Bohren KM . Mechanism of human aldehyde reductase: characterization of the active site pocket . Biochemistry . 34 . 35 . 11264–75 . September 1995 . 7669785 . 10.1021/bi00035a036 .
• Takahashi M, Lu YB, Myint T, Fujii J, Wada Y, Taniguchi N . In vivo glycation of aldehyde reductase, a major 3-deoxyglucosone reducing enzyme: identification of glycation sites . Biochemistry . 34 . 4 . 1433–8 . January 1995 . 7827091 . 10.1021/bi00004a038 .
• Robinson B, Hunsaker LA, Stangebye LA, Vander Jagt DL . Aldose and aldehyde reductases from human kidney cortex and medulla . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1203 . 2 . 260–6 . December 1993 . 8268209 . 10.1016/0167-4838(93)90092-6 .
• Sato S, Lin LR, Reddy VN, Kador PF . Aldose reductase in human retinal pigment epithelial cells . Experimental Eye Research . 57 . 2 . 235–41 . August 1993 . 8405190 . 10.1006/exer.1993.1119 .
• Udovikova EA, Wojtczak L . Mitochondrial aldehyde reductase: identification and characterization in rat liver and kidney cortex . The International Journal of Biochemistry & Cell Biology . 30 . 5 . 597–608 . May 1998 . 9693960 . 10.1016/S1357-2725(97)00143-X .
• Barski OA, Gabbay KH, Bohren KM . Characterization of the human aldehyde reductase gene and promoter . Genomics . 60 . 2 . 188–98 . September 1999 . 10486210 . 10.1006/geno.1999.5915 .
• O'connor T, Ireland LS, Harrison DJ, Hayes JD . Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members . The Biochemical Journal . 343 Pt 2 . 2. 487–504 . October 1999 . 10510318 . 1220579 . 10.1042/bj3430487 .
• Picklo MJ, Olson SJ, Markesbery WR, Montine TJ . Expression and activities of aldo-keto oxidoreductases in Alzheimer disease . Journal of Neuropathology and Experimental Neurology . 60 . 7 . 686–95 . July 2001 . 11444797 . 10.1093/jnen/60.7.686. free .
• Laclau M, Lu F, MacDonald MJ . Enzymes in pancreatic islets that use NADP(H) as a cofactor including evidence for a plasma membrane aldehyde reductase . Molecular and Cellular Biochemistry . 225 . 1– . 151–60 . September 2001 . 11716357 . 10.1023/A:1012238709063 . 38935230 .
• Lehner B, Sanderson CM . A protein interaction framework for human mRNA degradation . Genome Research . 14 . 7 . 1315–23 . July 2004 . 15231747 . 442147 . 10.1101/gr.2122004 .
• El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG, DeLucas LJ . Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications . Acta Crystallographica Section D . 50 . Pt 6 . 859–68 . November 1994 . 15299353 . 10.1107/S0907444994005275 . free . 1994AcCrD..50..859E .
• Bohren KM, Brownlee JM, Milne AC, Gabbay KH, Harrison DH . The structure of Apo R268A human aldose reductase: hinges and latches that control the kinetic mechanism . Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics . 1748 . 2 . 201–12 . May 2005 . 15769597 . 10.1016/j.bbapap.2005.01.006 .

Notes and References

1. Bohren KM, Bullock B, Wermuth B, Gabbay KH . The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases . The Journal of Biological Chemistry . 264 . 16 . 9547–51 . June 1989 . 10.1016/S0021-9258(18)60566-6 . 2498333 . free .
2. Fujii J, Hamaoka R, Matsumoto A, Fujii T, Yamaguchi Y, Egashira M, Miyoshi O, Niikawa N, Taniguchi N . The structural organization of the human aldehyde reductase gene, AKR1A1, and mapping to chromosome 1p33→p32 . Cytogenetics and Cell Genetics . 84 . 3–4 . 230–2 . Jul 1999 . 10393438 . 10.1159/000015265 . 34254843 .
3. Web site: Entrez Gene: AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase).
4. Palackal NT, Burczynski ME, Harvey RG, Penning TM . Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1) . Chemico-Biological Interactions . 130-132 . 1–3 . 815–24 . January 2001 . 11306097 . 10.1016/s0009-2797(00)00237-4. 2001CBI...130..815P .
5. Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P, Chanock S . Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma . Human Genetics . 121 . 2 . 161–8 . April 2007 . 17149600 . 10.1007/s00439-006-0288-9 . 11078978 .
6. El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG, DeLucas LJ . Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications . Acta Crystallographica Section D . 50 . Pt 6 . 859–68 . November 1994 . 15299353 . 10.1107/S0907444994005275 . free . 1994AcCrD..50..859E .
7. O'connor T, Ireland LS, Harrison DJ, Hayes JD . Major differences exist in the function and tissue-specific expression of human aflatoxin B1 aldehyde reductase and the principal human aldo-keto reductase AKR1 family members . The Biochemical Journal . 343 Pt 2 . 2 . 487–504 . October 1999 . 10510318 . 1220579 . 10.1042/bj3430487.
8. Penning TM, Drury JE . Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms . Archives of Biochemistry and Biophysics . 464 . 2 . 241–50 . August 2007 . 17537398 . 2025677 . 10.1016/j.abb.2007.04.024 .
9. Feather MS, Flynn TG, Munro KA, Kubiseski TJ, Walton DJ . Catalysis of reduction of carbohydrate 2-oxoaldehydes (osones) by mammalian aldose reductase and aldehyde reductase . Biochimica et Biophysica Acta (BBA) - General Subjects . 1244 . 1 . 10–6 . May 1995 . 7766643 . 10.1016/0304-4165(94)00156-r.
10. Bohren KM, Page JL, Shankar R, Henry SP, Gabbay KH . Expression of human aldose and aldehyde reductases. Site-directed mutagenesis of a critical lysine 262 . The Journal of Biological Chemistry . 266 . 35 . 24031–7 . December 1991 . 10.1016/S0021-9258(18)54387-8 . 1748675 . free .
11. Petrash JM, Srivastava SK . Purification and properties of human liver aldehyde reductases . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 707 . 1 . 105–14 . September 1982 . 6753936 . 10.1016/0167-4838(82)90402-2.
12. Li D, Zhang Q, Zhou L, Liu R . [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 . 29 . 3 . 273–6 . March 2013 . 23643085 .
13. Bains OS, Takahashi RH, Pfeifer TA, Grigliatti TA, Reid RE, Riggs KW . Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin . Drug Metabolism and Disposition . 36 . 5 . 904–10 . May 2008 . 18276838 . 10.1124/dmd.107.018895 . 14214962 .