AKR1B1 explained

Aldo-keto reductase family 1, member B1 (AKR1B1) is an gene in humans that encodes the enzyme aldose reductase.^{[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 of AKR1B1 in oxidative stress diseases, cell signal transduction, and cell proliferation process endows AKR1B1 with potential as a therapeutic target.

Structure

Gene

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.

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 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.^[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.

Interactions

AKR1B1 has been found to interact with:

• ginsenoside 20(S)-Rh2^[11]
• alkaloid^[12]
• carboxylic acid derivatives
• spirohydantoins
• cyclic amides

Further reading

• Borhani DW, Harter TM, Petrash JM . The crystal structure of the aldose reductase.NADPH binary complex . The Journal of Biological Chemistry . 267 . 34 . 24841–7 . December 1992 . 1447221 . 10.2210/pdb1abn/pdb.
• Wilson DK, Bohren KM, Gabbay KH, Quiocho FA . 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 . July 1992 . 1621098 . 10.1126/science.1621098 .
• Graham A, Heath P, Morten JE, Markham AF . The human aldose reductase gene maps to chromosome region 7q35 . Human Genetics . 86 . 5 . 509–14 . March 1991 . 1901827 . 10.1007/BF00194644 . 34446965 .
• Graham A, Brown L, Hedge PJ, Gammack AJ, Markham AF . Structure of the human aldose reductase gene . The Journal of Biological Chemistry . 266 . 11 . 6872–7 . April 1991 . 10.1016/S0021-9258(20)89582-9 . 1901857 . free .
• Grundmann U, Bohn H, Obermeier R, Amann E . Cloning and prokaryotic expression of a biologically active human placental aldose reductase . DNA and Cell Biology . 9 . 3 . 149–57 . April 1990 . 2111143 . 10.1089/dna.1990.9.149 .
• Nishimura C, Matsuura Y, Kokai Y, Akera T, Carper D, Morjana N, Lyons C, Flynn TG . Cloning and expression of human aldose reductase . The Journal of Biological Chemistry . 265 . 17 . 9788–92 . June 1990 . 10.1016/S0021-9258(19)38740-X . 2112546 . free .
• Morjana NA, Lyons C, Flynn TG . 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 . February 1989 . 10.1016/S0021-9258(19)81699-X . 2492527 . free .
• 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 .
• Chung S, LaMendola J . Cloning and sequence determination of human placental aldose reductase gene . The Journal of Biological Chemistry . 264 . 25 . 14775–7 . September 1989 . 10.1016/S0021-9258(18)63766-4 . 2504709 . free .
• Graham A, Hedge PJ, Powell SJ, Riley J, Brown L, Gammack A, Carey F, Markham AF . Nucleotide sequence of cDNA for human aldose reductase . Nucleic Acids Research . 17 . 20 . 8368 . October 1989 . 2510130 . 334974 . 10.1093/nar/17.20.8368 .
• Akagi Y, Kador PF, Kuwabara T, Kinoshita JH . Aldose reductase localization in human retinal mural cells . Investigative Ophthalmology & Visual Science . 24 . 11 . 1516–9 . November 1983 . 6417042 .
• Ko BC, Lam KS, Wat NM, Chung SS . 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 . July 1995 . 7789640 . 10.2337/diabetes.44.7.727 .
• Wilson DK, Tarle I, Petrash JM, Quiocho FA . Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat . Proceedings of the National Academy of Sciences of the United States of America . 90 . 21 . 9847–51 . November 1993 . 8234324 . 47669 . 10.1073/pnas.90.21.9847 . free . 1993PNAS...90.9847W .
• Tarle I, Borhani DW, Wilson DK, Quiocho FA, Petrash JM . 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 . December 1993 . 10.1016/S0021-9258(19)74444-5 . 8245005 . free .
• 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 .
• Jaquinod M, Potier N, Klarskov K, Reymann JM, Sorokine O, Kieffer S, Barth P, Andriantomanga V, Biellmann JF, Van Dorsselaer A . Sequence of pig lens aldose reductase and electrospray mass spectrometry of non-covalent and covalent complexes . European Journal of Biochemistry . 218 . 3 . 893–903 . December 1993 . 8281941 . 10.1111/j.1432-1033.1993.tb18445.x . free .
• Liu SQ, Bhatnagar A, Ansari NH, Srivastava SK . Identification of the reactive cysteine residue in human placenta aldose reductase . Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology . 1164 . 3 . 268–72 . August 1993 . 8343525 . 10.1016/0167-4838(93)90258-S .
• Nishimura C, Furue M, Ito T, Omori Y, Tanimoto T . Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay. Immunoassay of human aldose reductase . Biochemical Pharmacology . 46 . 1 . 21–8 . July 1993 . 8347133 . 10.1016/0006-2952(93)90343-U .
• 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 .
• Ferraretto A, Negri A, Giuliani A, De Grada L, Fuhrman Conti AM, Ronchi S . Aldose reductase is involved in long-term adaptation of EUE cells to hyperosmotic stress . Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . 1175 . 3 . 283–8 . February 1993 . 8435445 . 10.1016/0167-4889(93)90218-E .

Notes and References

1. Graham A, Heath P, Morten JE, Markham AF . The human aldose reductase gene maps to chromosome region 7q35 . Human Genetics . 86 . 5 . 509–14 . March 1991 . 1901827 . 10.1007/BF00194644 . 34446965 .
2. Web site: Entrez Gene: AKR1B1 aldo-keto reductase family 1, member B1 (aldose reductase).
3. Lee H . The structure and function of yeast xylose (aldose) reductases . Yeast . 14 . 11 . 977–84 . August 1998 . 9730277 . 10.1002/(sici)1097-0061(199808)14:11<977::aid-yea302>3.0.co;2-j. 39792612 .
4. 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.
5. Lefrançois-Martinez AM, Bertherat J, Val P, Tournaire C, Gallo-Payet N, Hyndman D, Veyssière G, Bertagna X, Jean C, Martinez A . 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 . June 2004 . 15181092 . 10.1210/jc.2003-031830 . free .
6. 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 . 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 . May 2014 . 24631337 . 10.1016/j.exer.2014.03.001 .
7. Zhou M, Zhang P, Xu X, Sun X . The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis . Investigative Ophthalmology & Visual Science . 56 . 4 . 2279–89 . April 2015 . 25722213 . 10.1167/iovs.14-16279 . free .
8. Grewal AS, Bhardwaj S, Pandita D, Lather V, Sekhon BS . Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases . Mini Reviews in Medicinal Chemistry . 16 . 2 . 120–62 . 2016-01-01 . 26349493 . 10.2174/1389557515666150909143737.
9. Maccari R, Ottanà R . 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 . March 2015 . 25375908 . 10.1021/jm500907a .
10. Chang KC, Ponder J, Labarbera DV, Petrash JM . Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia . Investigative Ophthalmology & Visual Science . 55 . 5 . 2853–61 . May 2014 . 24677107 . 4010364 . 10.1167/iovs.13-13487 .
11. Fatmawati S, Ersam T, Yu H, Zhang C, Jin F, Shimizu K . 20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng . Bioorganic & Medicinal Chemistry Letters . 24 . 18 . 4407–9 . September 2014 . 25152999 . 10.1016/j.bmcl.2014.08.009 .
12. Gupta S, Singh N, Jaggi AS . Alkaloids as aldose reductase inhibitors, with special reference to berberine . Journal of Alternative and Complementary Medicine . 20 . 3 . 195–205 . March 2014 . 24236461 . 10.1089/acm.2013.0088 .