Aldo-keto reductase family 1, member B1 (AKR1B1) is an gene in humans that encodes the enzymealdose 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
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.[6]
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.[7]
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.[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
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]
^"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.
^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. S2CID34446965.
^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.
^ abcdeGrewal 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. doi:10.2210/pdb1abn/pdb. 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. S2CID34446965.
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.
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.
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 (BBA) - Protein Structure and Molecular Enzymology. 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 (BBA) - Molecular Cell Research. 1175 (3): 283–8. doi:10.1016/0167-4889(93)90218-E. PMID8435445.
1abn: THE CRYSTAL STRUCTURE OF THE ALDOSE REDUCTASE NADPH BINARY COMPLEX
1ads: AN UNLIKELY SUGAR SUBSTRATE SITE IN THE 1.65 ANGSTROMS STRUCTURE OF THE HUMAN ALDOSE REDUCTASE HOLOENZYME IMPLICATED IN DIABETIC COMPLICATIONS
1az1: ALRESTATIN BOUND TO C298A/W219Y MUTANT HUMAN ALDOSE REDUCTASE
1az2: CITRATE BOUND, C298A/W219Y MUTANT HUMAN ALDOSE REDUCTASE
1ef3: FIDARESTAT BOUND TO HUMAN ALDOSE REDUCTASE
1el3: HUMAN ALDOSE REDUCTASE COMPLEXED WITH IDD384 INHIBITOR
1iei: CRYSTAL STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE INHIBITOR ZENARESTAT.
1mar: REFINED 1.8 ANGSTROMS STRUCTURE OF HUMAN ALDOSE REDUCTASE COMPLEXED WITH THE POTENT INHIBITOR ZOPOLRESTAT
1pwl: Crystal structure of human Aldose Reductase complexed with NADP and Minalrestat
1pwm: Crystal structure of human Aldose Reductase complexed with NADP and Fidarestat
1t40: Crystal structure of human aldose reductase complexed with NADP and IDD552 at ph 5
1t41: Crystal structure of human aldose reductase complexed with NADP and IDD552
1us0: HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP+ AND THE INHIBITOR IDD594 AT 0.66 ANGSTROM
1x96: Crystal structure of Aldose Reductase with citrates bound in the active site
1x97: Crystal structure of Aldose Reductase complexed with 2R4S (Stereoisomer of Fidarestat, 2S4S)
1x98: Crystal structure of Aldose Reductase complexed with 2S4R (Stereoisomer of Fidarestat, 2S4S)
1xgd: Apo R268A human aldose reductase
1z3n: Human aldose reductase in complex with NADP+ and the inhibitor lidorestat at 1.04 angstrom
1z89: Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor
1z8a: Human Aldose Reductase complexed with novel Sulfonyl-pyridazinone Inhibitor
2acq: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
2acr: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
2acs: AN ANION BINDING SITE IN HUMAN ALDOSE REDUCTASE: MECHANISTIC IMPLICATIONS FOR THE BINDING OF CITRATE, CACODYLATE, AND GLUCOSE-6-PHOSPHATE
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
2agt: Aldose Reductase Mutant Leu 300 Pro complexed with Fidarestat
2dux: Crystal structure of human Aldose Reductase complexed with zopolrestat after 3 days soaking (3days_soaked_1)
2duz: Human Aldose Reductase complexed with inhibitor zopolrestat after 3 days soaking (3days_soaked_2)
2dv0: Human Aldose Reductase complexed with zopolrestat after 6 days soaking(6days_soaked_2)
2f2k: Aldose reductase tertiary complex with NADPH and DEG
2fz8: Human Aldose reductase complexed with inhibitor zopolrestat at 1.48 A(1 day soaking).
2fz9: Human Aldose Reductase complexed with inhibitor zopolrestat after six days soaking.
2fzb: Human Aldose Reductase complexed with four tolrestat molecules at 1.5 A resolution.
2fzd: Human aldose reductase complexed with tolrestat at 1.08 A resolution.
2hv5: Human Aldose Reductase complexed with inhibitor zopolrestat after three days soaking (3days_soaked_3)
2hvn: Human Aldose Reductase-zopolrestat complex obtained by cocrystallisation after one day (1day_cocryst)
2hvo: Human Aldose Reductase-zopolrestat complex obtained by cocrystallisation (10days_cocryst)
2i16: Human aldose reductase in complex with NADP+ and the inhibitor IDD594 at temperature of 15K
2i17: Human aldose reductase in complex with NADP+ and the inhibitor IDD594 at temperature of 60K
2ikg: Aldose reductase complexed with nitrophenyl-oxadiazol type inhibitor at 1.43 A
2ikh: Human aldose reductase complexed with nitrofuryl-oxadiazol inhibitor at 1.55 A
2iki: Human aldose reductase complexed with halogenated IDD-type inhibitor
2ikj: Human aldose reductase complexed with nitro-substituted IDD-type inhibitor
2ine: Crystal Structure of Aldose Reductase complexed with Phenylacetic Acid
2inz: Crystal Structure of Aldose Reductase complexed with 2-Hydroxyphenylacetic Acid
2ipw: Crystal Structure of C298A W219Y Aldose Reductase complexed with Dichlorophenylacetic acid
2iq0: Crystal Structure of Aldose Reductase complexed with Hexanoic Acid
2iqd: Crystal Structure of Aldose Reductase complexed with Lipoic Acid
2is7: Crystal Structure of Aldose Reductase complexed with Dichlorophenylacetic acid
2isf: Crystal Structure of C298A W219Y Aldose Reductase complexed with Phenylacetic Acid
2j8t: HUMAN ALDOSE REDUCTASE IN COMPLEX WITH NADP AND CITRATE AT 0.82 ANGSTROM
2nvc: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (3)
2nvd: Human Aldose Reductase complexed with novel naphtho[1,2-d]isothiazole acetic acid derivative (2)
2pev: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution exceeds concentration of IDD594.
2pf8: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is equal to concentration of IDD594.
2pfh: Complex of Aldose Reductase with NADP+ and simultaneously bound competitive inhibitors Fidarestat and IDD594. Concentration of Fidarestat in soaking solution is less than concentration of IDD594.