Aldo-keto reductase family 1, member A1

Last updated
AKR1A1
PBB Protein AKR1A1 image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
Entrez

10327

58810

Ensembl

ENSG00000117448

ENSMUSG00000028692

UniProt

P14550

Q9JII6

RefSeq (mRNA)

NM_001202413
NM_001202414
NM_006066
NM_153326

NM_021473

RefSeq (protein)

NP_001189342
NP_001189343
NP_006057
NP_697021

NP_067448

Location (UCSC) Chr 1: 45.55 – 45.57 Mb Chr 4: 116.49 – 116.51 Mb
PubMed search [3] [4]
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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">4-Hydroxynonenal</span> Chemical compound

4-Hydroxynonenal, or 4-hydroxy-2E-nonenal or 4-hydroxy-2-nonenal or 4-HNE or HNE,, is an α,β-unsaturated hydroxyalkenal that is produced by lipid peroxidation in cells. 4-HNE is the primary α,β-unsaturated hydroxyalkenal formed in this process. It is a colorless oil. It is found throughout animal tissues, and in higher quantities during oxidative stress due to the increase in the lipid peroxidation chain reaction, due to the increase in stress events. 4-HNE has been hypothesized to play a key role in cell signal transduction, in a variety of pathways from cell cycle events to cellular adhesion.

Carboxy-lyases, also known as decarboxylases, are carbon–carbon lyases that add or remove a carboxyl group from organic compounds. These enzymes catalyze the decarboxylation of amino acids, beta-keto acids and alpha-keto acids.

<span class="mw-page-title-main">Aldose reductase</span> Enzyme

In enzymology, aldose reductase is a cytosolic NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of glucose to sorbitol, the first step in polyol pathway of glucose metabolism.

<span class="mw-page-title-main">3-hydroxyacyl-CoA dehydrogenase</span> Enzyme

In enzymology, a 3-hydroxyacyl-CoA dehydrogenase (EC 1.1.1.35) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">AKR1B1</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that is encoded by the AKR1B1 gene in humans. It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. The involvement of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

<span class="mw-page-title-main">AKR1C3</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member C3 (AKR1C3), also known as 17β-hydroxysteroid dehydrogenase type 5 or 3α-hydroxysteroid dehydrogenase type 2 (3α-HSD2) is a key steroidogenic enzyme that in humans is encoded by the AKR1C3 gene.

<span class="mw-page-title-main">AKR1C1</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member C1 also known as 20α-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, and dihydrodiol dehydrogenase 1/2 is an enzyme that in humans is encoded by the AKR1C1 gene.

<span class="mw-page-title-main">CBR1</span> Protein-coding gene in the species Homo sapiens

Carbonyl reductase 1, also known as CBR1, is an enzyme which in humans is encoded by the CBR1 gene. The protein encoded by this gene belongs to the short-chain dehydrogenases/reductases (SDR) family, which function as NADPH-dependent oxidoreductases having wide specificity for carbonyl compounds, such as quinones, prostaglandins, and various xenobiotics. Alternatively spliced transcript variants have been found for this gene.

<span class="mw-page-title-main">Adrenodoxin reductase</span> Protein-coding gene in the species Homo sapiens

Adrenodoxin reductase, was first isolated from bovine adrenal cortex where it functions as the first enzyme in the mitochondrial P450 systems that catalyze essential steps in steroid hormone biosynthesis. Examination of complete genome sequences revealed that adrenodoxin reductase gene is present in most metazoans and prokaryotes.

<span class="mw-page-title-main">3α-Hydroxysteroid dehydrogenase</span> Protein-coding gene in the species Homo sapiens

3α-Hydroxysteroid dehydrogenase type 1 (3α-HSD1) or aldo-keto reductase family 1 member C4 is an enzyme that in humans is encoded by the AKR1C4 gene. It is known to be necessary for the synthesis of the endogenous neurosteroids allopregnanolone, THDOC, and 3α-androstanediol. It is also known to catalyze the reversible conversion of 3α-androstanediol (5α-androstane-3α,17β-diol) to dihydrotestosterone and vice versa.

<span class="mw-page-title-main">AKR1B10</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member B10 is an enzyme that in humans is encoded by the AKR1B10 gene.

<span class="mw-page-title-main">AKR7A2</span> Protein-coding gene in the species Homo sapiens

Aflatoxin B1 aldehyde reductase member 2 is an enzyme that in humans is encoded by the AKR7A2 gene.

<span class="mw-page-title-main">Aldo-keto reductase</span> Protein family

The aldo-keto reductase family is a family of proteins that are subdivided into 16 categories; these include a number of related monomeric NADPH-dependent oxidoreductases, such as aldehyde reductase, aldose reductase, prostaglandin F synthase, xylose reductase, rho crystallin, and many others.

<span class="mw-page-title-main">Alrestatin</span> Chemical compound

Alrestatin is an inhibitor of aldose reductase, an enzyme involved in the pathogenesis of complications of diabetes mellitus, including diabetic neuropathy.

5β-Reductase, or Δ4-3-oxosteroid 5β-reductase (EC 1.3.1.3, 3-oxo-Δ4-steroid 5β-reductase, androstenedione 5β-reductase, cholestenone 5β-reductase, cortisone 5β-reductase, cortisone Δ4-5β-reductase, steroid 5β-reductase, testosterone 5β-reductase, Δ4-3-ketosteroid 5β-reductase, Δ4-5β-reductase, Δ4-hydrogenase, 4,5β-dihydrocortisone:NADP+ Δ4-oxidoreductase, 3-oxo-5β-steroid:NADP+ Δ4-oxidoreductase) is an enzyme with systematic name 5β-cholestan-3-one:NADP+ 4,5-oxidoreductase. This enzyme catalyses the following chemical reaction

FMN reductase (NADH) (EC 1.5.1.42, NADH-FMN reductase) is an enzyme with systematic name FMNH2:NAD+ oxidoreductase. This enzyme catalyses the following chemical reaction

Peptide-methionine (S)-S-oxide reductase (EC 1.8.4.11, MsrA, methionine sulphoxide reductase A, methionine S-oxide reductase (S-form oxidizing), methionine sulfoxide reductase A, peptide methionine sulfoxide reductase, formerly protein-methionine-S-oxide reductase) is an enzyme with systematic name peptide-L-methionine:thioredoxin-disulfide S-oxidoreductase (L-methionine (S)-S-oxide-forming). This enzyme catalyses the following chemical reaction

Taurochenodeoxycholate 6alpha-hydroxylase (EC 1.14.13.97, CYP3A4, CYP4A21, taurochenodeoxycholate 6alpha-monooxygenase) is an enzyme with systematic name taurochenodeoxycholate,NADPH:oxygen oxidoreductase (6alpha-hydroxylating). This enzyme catalyses the following chemical reaction

<span class="mw-page-title-main">AKR1C2</span> Protein-coding gene in the species Homo sapiens

Aldo-keto reductase family 1 member C2, also known as bile acid binding protein, 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD3), and dihydrodiol dehydrogenase type 2, is an enzyme that in humans is encoded by the AKR1C2 gene.

In enzymology, a prostaglandin-F synthase (PGFS; EC 1.1.1.188) is an enzyme that catalyzes the chemical reaction:

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000117448 - Ensembl, May 2017
  2. 1 2 3 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.
  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.
  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.
  7. 1 2 "Entrez Gene: AKR1A1 aldo-keto reductase family 1, member A1 (aldehyde reductase)".
  8. 1 2 3 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.
  9. 1 2 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.
  11. 1 2 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.
  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.
  16. 1 2 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.
  17. 1 2 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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