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AKR1B1

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AKR1B1
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesAKR1B1, ADR, ALDR1, ALR2, AR, aldo-keto reductase family 1, member B1 (aldose reductase), aldo-keto reductase family 1 member B
External IDsOMIM: 103880; MGI: 1353494; HomoloGene: 133743; GeneCards: AKR1B1; OMA:AKR1B1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

231

11677

Ensembl

ENSG00000085662

ENSMUSG00000001642

UniProt

P15121

P45376

RefSeq (mRNA)

NM_001628
NM_001346142

NM_009658

RefSeq (protein)

NP_001333071
NP_001619

NP_033788

Location (UCSC)Chr 7: 134.44 – 134.46 MbChr 6: 34.28 – 34.29 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Aldo-keto reductase family 1, member B1 (AKR1B1) is an gene in humans that encodes the enzyme aldose reductase.[5][6] 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.

Structure

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Gene

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The AKR1B1 gene lies on the chromosome location of 7q33 and consists of 10 exons. There are a few putative pseudogenes for this gene, and one of them has been confirmed and mapped to chromosome 3.[6]

Protein

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AKR1B1 consists of 316 amino acid residues and weighs 35853Da. It does not possess the traditional dinucleotide binding fold. The way it binds NADPH differs from other nucleotide adenine dinucleotide-dependent enzymes. The active site pocket of human aldose reductase is relatively hydrophobic, lined by seven aromatic and four other non-polar residues.[7]

Function

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AR belongs to the aldehyde-keto reductase superfamily, with a widely expression in human organs including the kidney, lens, retina, nerve, heart, placenta, brain, skeletal muscle, testis, blood vessels, lung, and liver.[8] It is a reduced nicotinamide-adenine dinucleotide phosphate (NADPH)-dependent enzyme catalyzing the reduction of various aldehydes and ketones to the corresponding alcohol. It also participates in glucose metabolism and osmoregulation and plays a protective role against toxic aldehydes derived from lipid peroxidation and steroidogenesis.[9]

Clinical significance

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Under diabetic conditions AR converts glucose into sorbitol, which is then converted to fructose. 20466987 It has been found to play an important role in many diabetes complications such as diabetes retinopathy and renopathy.[10][11][12] It is also involved in many oxidative stress diseases, cell signal transduction, and cell proliferation process including cardiovascular disorders, sepsis, and cancer.[13]

It has been reported that the action of AR contributes to the activation of retinal microglia, suggesting that inhibition of AR may be of a therapeutic importance to reduce inflammation associated with activation of RMG.[14] Adapting AR inhibitors could as well prevent sepsis complications, prevent angiogenesis, ameliorate mild or asymptomatic diabetic cardiovascular autonomic neuropathy and may be a promising strategy for the treatment of endotoxemia and other ROS-induced inflammatory diseases.[12]

Interactions

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AKR1B1 has been found to interact with:

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000085662 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000001642 – 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. ^ Graham A, Heath P, Morten JE, Markham AF (March 1991). "The human aldose reductase gene maps to chromosome region 7q35". Human Genetics. 86 (5): 509–14. doi:10.1007/BF00194644. PMID 1901827. S2CID 34446965.
  6. ^ a b "Entrez Gene: AKR1B1 aldo-keto reductase family 1, member B1 (aldose reductase)".
  7. ^ Lee H (August 1998). "The structure and function of yeast xylose (aldose) reductases". Yeast. 14 (11): 977–84. doi:10.1002/(sici)1097-0061(199808)14:11<977::aid-yea302>3.0.co;2-j. PMID 9730277. S2CID 39792612.
  8. ^ 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.
  9. ^ Lefrançois-Martinez AM, Bertherat J, Val P, Tournaire C, Gallo-Payet N, Hyndman D, Veyssière G, Bertagna X, Jean C, Martinez A (June 2004). "Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors". The Journal of Clinical Endocrinology and Metabolism. 89 (6): 3010–9. doi:10.1210/jc.2003-031830. PMID 15181092.
  10. ^ Park J, Kim H, Park SY, Lim SW, Kim YS, Lee DH, Roh GS, Kim HJ, Kang SS, Cho GJ, Jeong BY, Kwon HM, Choi WS (May 2014). "Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy". Experimental Eye Research. 122: 13–9. doi:10.1016/j.exer.2014.03.001. PMID 24631337.
  11. ^ Zhou M, Zhang P, Xu X, Sun X (April 2015). "The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis". Investigative Ophthalmology & Visual Science. 56 (4): 2279–89. doi:10.1167/iovs.14-16279. PMID 25722213.
  12. ^ a b c d e Grewal AS, Bhardwaj S, Pandita D, Lather V, Sekhon BS (2016-01-01). "Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases". Mini Reviews in Medicinal Chemistry. 16 (2): 120–62. doi:10.2174/1389557515666150909143737. PMID 26349493.
  13. ^ Maccari R, Ottanà R (March 2015). "Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions". Journal of Medicinal Chemistry. 58 (5): 2047–67. doi:10.1021/jm500907a. PMID 25375908.
  14. ^ Chang KC, Ponder J, Labarbera DV, Petrash JM (May 2014). "Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia". Investigative Ophthalmology & Visual Science. 55 (5): 2853–61. doi:10.1167/iovs.13-13487. PMC 4010364. PMID 24677107.
  15. ^ Fatmawati S, Ersam T, Yu H, Zhang C, Jin F, Shimizu K (September 2014). "20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng". Bioorganic & Medicinal Chemistry Letters. 24 (18): 4407–9. doi:10.1016/j.bmcl.2014.08.009. PMID 25152999.
  16. ^ Gupta S, Singh N, Jaggi AS (March 2014). "Alkaloids as aldose reductase inhibitors, with special reference to berberine". Journal of Alternative and Complementary Medicine. 20 (3): 195–205. doi:10.1089/acm.2013.0088. PMID 24236461.

Further reading

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