Aldo-keto reductase family 1, member B1 (AKR1B1), also known as aldose reductase, is an enzyme that in humans is encoded by the AKR1B1gene.[1][2] 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 in oxidative stress diseases, cell signal transduction and cell proliferation process endows AKR1B1 the potential as a therapeutic target.
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.[2]
Protein
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.[3]
Function
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.[4] 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.[5]
Clinical significance
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.[6][7][8] It is also involved in many oxidative stress diseases, cell signal transduction and cell proliferation process including cardiovascular disorders, sepsis, and cancer.[9]
It has been reported that he 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.[10] 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.[8]
↑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. PMID1901827.
↑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. PMID15181092.
↑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. PMID24631337.
↑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. PMID25722213.
↑ 8.08.18.28.38.4Grewal 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. PMID26349493.
↑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. PMID25375908.
↑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. PMID25152999.
↑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. PMID24236461.
Further reading
Borhani DW, Harter TM, Petrash JM (December 1992). "The crystal structure of the aldose reductase.NADPH binary complex". The Journal of Biological Chemistry. 267 (34): 24841–7. PMID1447221.
Wilson DK, Bohren KM, Gabbay KH, Quiocho FA (July 1992). "An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications". Science. 257 (5066): 81–4. doi:10.1126/science.1621098. PMID1621098.
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. PMID1901827.
Graham A, Brown L, Hedge PJ, Gammack AJ, Markham AF (April 1991). "Structure of the human aldose reductase gene". The Journal of Biological Chemistry. 266 (11): 6872–7. PMID1901857.
Grundmann U, Bohn H, Obermeier R, Amann E (April 1990). "Cloning and prokaryotic expression of a biologically active human placental aldose reductase". DNA and Cell Biology. 9 (3): 149–57. doi:10.1089/dna.1990.9.149. PMID2111143.
Nishimura C, Matsuura Y, Kokai Y, Akera T, Carper D, Morjana N, Lyons C, Flynn TG (June 1990). "Cloning and expression of human aldose reductase". The Journal of Biological Chemistry. 265 (17): 9788–92. PMID2112546.
Morjana NA, Lyons C, Flynn TG (February 1989). "Aldose reductase from human psoas muscle. Affinity labeling of an active site lysine by pyridoxal 5'-phosphate and pyridoxal 5'-diphospho-5'-adenosine". The Journal of Biological Chemistry. 264 (5): 2912–9. PMID2492527.
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. PMID2498333.
Chung S, LaMendola J (September 1989). "Cloning and sequence determination of human placental aldose reductase gene". The Journal of Biological Chemistry. 264 (25): 14775–7. PMID2504709.
Akagi Y, Kador PF, Kuwabara T, Kinoshita JH (November 1983). "Aldose reductase localization in human retinal mural cells". Investigative Ophthalmology & Visual Science. 24 (11): 1516–9. PMID6417042.
Ko BC, Lam KS, Wat NM, Chung SS (July 1995). "An (A-C)n dinucleotide repeat polymorphic marker at the 5' end of the aldose reductase gene is associated with early-onset diabetic retinopathy in NIDDM patients". Diabetes. 44 (7): 727–32. doi:10.2337/diabetes.44.7.727. PMID7789640.
Tarle I, Borhani DW, Wilson DK, Quiocho FA, Petrash JM (December 1993). "Probing the active site of human aldose reductase. Site-directed mutagenesis of Asp-43, Tyr-48, Lys-77, and His-110". The Journal of Biological Chemistry. 268 (34): 25687–93. PMID8245005.
Robinson B, Hunsaker LA, Stangebye LA, Vander Jagt DL (December 1993). "Aldose and aldehyde reductases from human kidney cortex and medulla". Biochimica et Biophysica Acta. 1203 (2): 260–6. doi:10.1016/0167-4838(93)90092-6. PMID8268209.
Jaquinod M, Potier N, Klarskov K, Reymann JM, Sorokine O, Kieffer S, Barth P, Andriantomanga V, Biellmann JF, Van Dorsselaer A (December 1993). "Sequence of pig lens aldose reductase and electrospray mass spectrometry of non-covalent and covalent complexes". European Journal of Biochemistry. 218 (3): 893–903. doi:10.1111/j.1432-1033.1993.tb18445.x. PMID8281941.
Liu SQ, Bhatnagar A, Ansari NH, Srivastava SK (August 1993). "Identification of the reactive cysteine residue in human placenta aldose reductase". Biochimica et Biophysica Acta. 1164 (3): 268–72. doi:10.1016/0167-4838(93)90258-S. PMID8343525.
Nishimura C, Furue M, Ito T, Omori Y, Tanimoto T (July 1993). "Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay. Immunoassay of human aldose reductase". Biochemical Pharmacology. 46 (1): 21–8. doi:10.1016/0006-2952(93)90343-U. PMID8347133.
Sato S, Lin LR, Reddy VN, Kador PF (August 1993). "Aldose reductase in human retinal pigment epithelial cells". Experimental Eye Research. 57 (2): 235–41. doi:10.1006/exer.1993.1119. PMID8405190.
Ferraretto A, Negri A, Giuliani A, De Grada L, Fuhrman Conti AM, Ronchi S (February 1993). "Aldose reductase is involved in long-term adaptation of EUE cells to hyperosmotic stress". Biochimica et Biophysica Acta. 1175 (3): 283–8. doi:10.1016/0167-4889(93)90218-E. PMID8435445.
2acu: TYROSINE-48 IS THE PROTON DONOR AND HISTIDINE-110 DIRECTS SUBSTRATE STEREOCHEMICAL SELECTIVITY IN THE REDUCTION REACTION OF HUMAN ALDOSE REDUCTASE: ENZYME KINETICS AND THE CRYSTAL STRUCTURE OF THE Y48H MUTANT ENZYME
2pev: Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution exceeds concentration of IDD594.
2pf8: Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is equal to concentration of IDD594.
2pfh: Complex of Aldose Reductase with NADP+ and simaltaneously bound competetive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is less than concentration of IDD594.
![2nvc: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)](/index.php?title=Special:Upload&wpDestFile=PDB_2nvc_EBI.jpg){kind=link}
![2nvd: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (2)](/index.php?title=Special:Upload&wpDestFile=PDB_2nvd_EBI.jpg){kind=link}
