Aldo-keto reductase family 1, member A1

AKR1A1
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2ALR
Identifiers
Aliases	AKR1A1, ALDR1, ALR, ARM, DD3, HEL-S-6, Aldo-keto reductase family 1, member A1, aldo-keto reductase family 1, member A1 (aldehyde reductase), aldo-keto reductase family 1 member A1
External IDs	OMIM: 103830; MGI: 1929955; HomoloGene: 74565; GeneCards: AKR1A1; OMA:AKR1A1 - orthologs
Gene location (Human)
Chr.	Chromosome 1 (human)
End	45,570,049 bp
Gene location (Mouse)
Chr.	Chromosome 4 (mouse)
End	116,508,877 bp
RNA expression pattern
	Top expressed in
	kidney tubule; ; nasal epithelium; ; mucosa of ileum; ; right lobe of liver; ; palpebral conjunctiva; ; human kidney; ; body of pancreas; ; glomerulus; ; mucosa of transverse colon; ; parotid gland;
	Top expressed in
	barrel cortex; ; vestibular sensory epithelium; ; medullary collecting duct; ; Epithelium of choroid plexus; ; external carotid artery; ; utricle; ; superior cervical ganglion; ; condyle; ; conjunctival fornix; ; iris;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	alditol:NADP+ 1-oxidoreductase activity; electron transfer activity; oxidoreductase activity; alcohol dehydrogenase (NADP+) activity; protein binding; aldo-keto reductase (NADP) activity; L-glucuronate reductase activity; glucuronolactone reductase activity; NAD-retinol dehydrogenase activity; allyl-alcohol dehydrogenase activity;
Cellular component	cytosol; extracellular exosome; apical plasma membrane; extracellular space; synapse; cytoplasm; plasma membrane; membrane;
Biological process	cellular aldehyde metabolic process; aldehyde catabolic process; D-glucuronate catabolic process; L-ascorbic acid biosynthetic process; glutathione derivative biosynthetic process; glucuronate catabolic process to xylulose 5-phosphate; glucose metabolic process; electron transport chain; cellular detoxification of aldehyde; daunorubicin metabolic process; doxorubicin metabolic process;
	Sources:Amigo / QuickGO
Orthologs
	10327
	58810
	ENSG00000117448
	ENSMUSG00000028692
	P14550
	Q9JII6
	NM_001202413; NM_001202414; NM_006066; NM_153326
	NM_021473
	NP_001189342; NP_001189343; NP_006057; NP_697021
	NP_067448
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]^[7] 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.^[8] Mutations in the AKR1A1 gene has been found associated with non-Hodgkin's lymphoma.^[9]

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.^[10] Alternative splicing of this gene results in two transcript variants encoding the same protein.^[7]

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.^[11] 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.^[12] AKR1A1 is shown to demonstrate characteristically high specific activity towards many aromatic and aliphatic aldehydes,^[11] and preferentially catalyses the NADPH-dependent reduction of aliphatic aldehydes, aromatic aldehydes and biogenic amines.^[13]^[14]^[15] It is also reported to be involved in the metabolism of 4-hydroxynonenal and play a role in the resistance to oxidative stress.^[16]

Clinical significance

A SNP in intron 5 of AKR1A1 has been found to be significantly associated with increased risk of non-Hodgkin's lymphoma.^[9] AKR1A1 could activate procarcinogens, such as polycyclic aromatic hydrocarbon.^[8] 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.^[17]

Interactions

4-hydroxynonenal ^[16]

polycyclic aromatic hydrocarbon^[8]

DAUN ^[17]

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000117448 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000028692 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ Bohren KM, Bullock B, Wermuth B, Gabbay KH (June 1989). "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. doi:10.1016/S0021-9258(18)60566-6. PMID 2498333.
^ Fujii J, Hamaoka R, Matsumoto A, Fujii T, Yamaguchi Y, Egashira M, Miyoshi O, Niikawa N, Taniguchi N (Jul 1999). "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. doi:10.1159/000015265. PMID 10393438. S2CID 34254843.
^ ^a ^b "Entrez Gene: AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase)".
^ ^a ^b ^c Palackal NT, Burczynski ME, Harvey RG, Penning TM (January 2001). "Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1)". Chemico-Biological Interactions. 130–132 (1–3): 815–24. Bibcode:2001CBI...130..815P. doi:10.1016/s0009-2797(00)00237-4. PMID 11306097.
^ ^a ^b Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P, Chanock S (April 2007). "Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma". Human Genetics. 121 (2): 161–8. doi:10.1007/s00439-006-0288-9. PMID 17149600. S2CID 11078978.
^ El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG, DeLucas LJ (November 1994). "Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications". Acta Crystallographica Section D. 50 (Pt 6): 859–68. Bibcode:1994AcCrD..50..859E. doi:10.1107/S0907444994005275. PMID 15299353.
^ ^a ^b O'connor T, Ireland LS, Harrison DJ, Hayes JD (October 1999). "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. doi:10.1042/bj3430487. PMC 1220579. PMID 10510318.
^ Penning TM, Drury JE (August 2007). "Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms". Archives of Biochemistry and Biophysics. 464 (2): 241–50. doi:10.1016/j.abb.2007.04.024. PMC 2025677. PMID 17537398.
^ Feather MS, Flynn TG, Munro KA, Kubiseski TJ, Walton DJ (May 1995). "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. doi:10.1016/0304-4165(94)00156-r. PMID 7766643.
^ Bohren KM, Page JL, Shankar R, Henry SP, Gabbay KH (December 1991). "Expression of human aldose and aldehyde reductases. Site-directed mutagenesis of a critical lysine 262". The Journal of Biological Chemistry. 266 (35): 24031–7. doi:10.1016/S0021-9258(18)54387-8. PMID 1748675.
^ Petrash JM, Srivastava SK (September 1982). "Purification and properties of human liver aldehyde reductases". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 707 (1): 105–14. doi:10.1016/0167-4838(82)90402-2. PMID 6753936.
^ ^a ^b Li D, Zhang Q, Zhou L, Liu R (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. 29 (3): 273–6. PMID 23643085.
^ ^a ^b Bains OS, Takahashi RH, Pfeifer TA, Grigliatti TA, Reid RE, Riggs KW (May 2008). "Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin". Drug Metabolism and Disposition. 36 (5): 904–10. doi:10.1124/dmd.107.018895. PMID 18276838. S2CID 14214962.

External links

AKR1A1 human gene location in the UCSC Genome Browser.
AKR1A1 human gene details in the UCSC Genome Browser.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000117448 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000028692 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid2498333-5] Bohren KM, Bullock B, Wermuth B, Gabbay KH (June 1989). "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. doi:10.1016/S0021-9258(18)60566-6. PMID 2498333.

[pmid10393438-6] Fujii J, Hamaoka R, Matsumoto A, Fujii T, Yamaguchi Y, Egashira M, Miyoshi O, Niikawa N, Taniguchi N (Jul 1999). "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. doi:10.1159/000015265. PMID 10393438. S2CID 34254843.

[entrez-7] "Entrez Gene: AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase)".

[Palackal_2001-8] Palackal NT, Burczynski ME, Harvey RG, Penning TM (January 2001). "Metabolic activation of polycyclic aromatic hydrocarbon trans-dihydrodiols by ubiquitously expressed aldehyde reductase (AKR1A1)". Chemico-Biological Interactions. 130–132 (1–3): 815–24. Bibcode:2001CBI...130..815P. doi:10.1016/s0009-2797(00)00237-4. PMID 11306097.

[Lan_2007-9] Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P, Chanock S (April 2007). "Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma". Human Genetics. 121 (2): 161–8. doi:10.1007/s00439-006-0288-9. PMID 17149600. S2CID 11078978.

[10] El-Kabbani O, Green NC, Lin G, Carson M, Narayana SV, Moore KM, Flynn TG, DeLucas LJ (November 1994). "Structures of human and porcine aldehyde reductase: an enzyme implicated in diabetic complications". Acta Crystallographica Section D. 50 (Pt 6): 859–68. Bibcode:1994AcCrD..50..859E. doi:10.1107/S0907444994005275. PMID 15299353.

[O'connor_1999-11] O'connor T, Ireland LS, Harrison DJ, Hayes JD (October 1999). "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. doi:10.1042/bj3430487. PMC 1220579. PMID 10510318.

[12] Penning TM, Drury JE (August 2007). "Human aldo-keto reductases: Function, gene regulation, and single nucleotide polymorphisms". Archives of Biochemistry and Biophysics. 464 (2): 241–50. doi:10.1016/j.abb.2007.04.024. PMC 2025677. PMID 17537398.

[13] Feather MS, Flynn TG, Munro KA, Kubiseski TJ, Walton DJ (May 1995). "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. doi:10.1016/0304-4165(94)00156-r. PMID 7766643.

[pmid1748675-14] Bohren KM, Page JL, Shankar R, Henry SP, Gabbay KH (December 1991). "Expression of human aldose and aldehyde reductases. Site-directed mutagenesis of a critical lysine 262". The Journal of Biological Chemistry. 266 (35): 24031–7. doi:10.1016/S0021-9258(18)54387-8. PMID 1748675.

[15] Petrash JM, Srivastava SK (September 1982). "Purification and properties of human liver aldehyde reductases". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 707 (1): 105–14. doi:10.1016/0167-4838(82)90402-2. PMID 6753936.

[Li_2013-16] Li D, Zhang Q, Zhou L, Liu R (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. 29 (3): 273–6. PMID 23643085.

[Bains_2008-17] Bains OS, Takahashi RH, Pfeifer TA, Grigliatti TA, Reid RE, Riggs KW (May 2008). "Two allelic variants of aldo-keto reductase 1A1 exhibit reduced in vitro metabolism of daunorubicin". Drug Metabolism and Disposition. 36 (5): 904–10. doi:10.1124/dmd.107.018895. PMID 18276838. S2CID 14214962.

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v t e Oxidoreductases: alcohol oxidoreductases (EC 1.1)
1.1.1: NAD/NADP acceptor	3-hydroxyacyl-CoA dehydrogenase 3-hydroxybutyryl-CoA dehydrogenase Alcohol dehydrogenase Aldo-keto reductase 1A1 1B1 1B10 1C1 1C3 1C4 7A2 Aldose reductase Beta-Ketoacyl ACP reductase Carbohydrate dehydrogenases Carnitine dehydrogenase D-malate dehydrogenase (decarboxylating) DXP reductoisomerase Glucose-6-phosphate dehydrogenase Glycerol-3-phosphate dehydrogenase HMG-CoA reductase IMP dehydrogenase Isocitrate dehydrogenase Lactate dehydrogenase L-threonine dehydrogenase L-xylulose reductase Malate dehydrogenase Malate dehydrogenase (decarboxylating) Malate dehydrogenase (NADP+) Malate dehydrogenase (oxaloacetate-decarboxylating) Malate dehydrogenase (oxaloacetate-decarboxylating) (NADP+) Phosphogluconate dehydrogenase Sorbitol dehydrogenase Hydroxysteroid dehydrogenase: 3β 3β-HSD NSDHL 11β 11β-HSD1 11β-HSD2 17β
1.1.2: cytochrome acceptor	D-lactate dehydrogenase (cytochrome) D-lactate dehydrogenase (cytochrome c-553) Mannitol dehydrogenase (cytochrome)
1.1.3: oxygen acceptor	Glucose oxidase L-gulonolactone oxidase Xanthine oxidase Alcohol oxidase
1.1.4: disulfide as acceptor	Vitamin K epoxide reductase Vitamin-K-epoxide reductase (warfarin-insensitive)
1.1.5: quinone/similar acceptor	Malate dehydrogenase (quinone) Quinoprotein glucose dehydrogenase
1.1.99: other acceptors	Choline dehydrogenase L2HGDH

v t e Enzymes
Activity	Active site Binding site Catalytic triad Oxyanion hole Enzyme promiscuity Diffusion-limited enzyme Cofactor Enzyme catalysis
Regulation	Allosteric regulation Cooperativity Enzyme inhibitor Enzyme activator
Classification	EC number Enzyme superfamily Enzyme family List of enzymes
Kinetics	Enzyme kinetics Eadie–Hofstee diagram Hanes–Woolf plot Lineweaver–Burk plot Michaelis–Menten kinetics
Types	EC1 Oxidoreductases (list) EC2 Transferases (list) EC3 Hydrolases (list) EC4 Lyases (list) EC5 Isomerases (list) EC6 Ligases (list) EC7 Translocases (list)