View source for AKR1B1

{{Infobox_gene}}
'''Aldo-keto reductase family 1, member B1''' ('''AKR1B1'''), also known as '''aldose reductase''', is an [[enzyme]] that in humans is encoded by the ''AKR1B1'' [[gene]].<ref name="pmid1901827">{{cite journal | vauthors = Graham A, Heath P, Morten JE, Markham AF | title = The human aldose reductase gene maps to chromosome region 7q35 | journal = Human Genetics | volume = 86 | issue = 5 | pages = 509–14 | date = March 1991 | pmid = 1901827 | doi = 10.1007/BF00194644 }}</ref><ref name="entrez">{{cite web|url=https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=231|title=Entrez Gene: AKR1B1 aldo-keto reductase family 1, member B1 (aldose reductase)|accessdate=}}</ref> 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.

== 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.<ref name="entrez" />

=== 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.<ref>{{cite journal | vauthors = Lee H | title = The structure and function of yeast xylose (aldose) reductases | journal = Yeast | volume = 14 | issue = 11 | pages = 977–84 | date = August 1998 | pmid = 9730277 | doi =  10.1002/(sici)1097-0061(199808)14:11<977::aid-yea302>3.0.co;2-j}}</ref>

== Function ==

AR belongs to the aldehyde-keto reductase [[superfamily (biology)|superfamily]], with a widely expression in human organs including the kidney, [[Lens (anatomy)|lens]], [[retina]], nerve, heart, placenta, brain, skeletal muscle, testis, blood vessels, lung, and liver.<ref>{{cite journal | vauthors = O'connor T, Ireland LS, Harrison DJ, Hayes JD | title = 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 | journal = The Biochemical Journal | volume = 343 Pt 2 | pages = 487–504 | date = October 1999 | pmid = 10510318 | pmc = 1220579 | doi=10.1042/bj3430487}}</ref>  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]].<ref>{{cite journal | vauthors = Lefrançois-Martinez AM, Bertherat J, Val P, Tournaire C, Gallo-Payet N, Hyndman D, Veyssière G, Bertagna X, Jean C, Martinez A | title = Decreased expression of cyclic adenosine monophosphate-regulated aldose reductase (AKR1B1) is associated with malignancy in human sporadic adrenocortical tumors | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 89 | issue = 6 | pages = 3010–9 | date = June 2004 | pmid = 15181092 | doi = 10.1210/jc.2003-031830 }}</ref>

== 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.<ref>{{cite journal | vauthors = 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 | title = Tonicity-responsive enhancer binding protein regulates the expression of aldose reductase and protein kinase C δ in a mouse model of diabetic retinopathy | journal = Experimental Eye Research | volume = 122 | pages = 13–9 | date = May 2014 | pmid = 24631337 | doi = 10.1016/j.exer.2014.03.001 }}</ref><ref>{{cite journal | vauthors = Zhou M, Zhang P, Xu X, Sun X | title = The Relationship Between Aldose Reductase C106T Polymorphism and Diabetic Retinopathy: An Updated Meta-Analysis | journal = Investigative Ophthalmology & Visual Science | volume = 56 | issue = 4 | pages = 2279–89 | date = April 2015 | pmid = 25722213 | doi = 10.1167/iovs.14-16279 }}</ref><ref name="Grewal_2016">{{cite journal | vauthors = Grewal AS, Bhardwaj S, Pandita D, Lather V, Sekhon BS | title = Updates on Aldose Reductase Inhibitors for Management of Diabetic Complications and Non-diabetic Diseases | journal = Mini Reviews in Medicinal Chemistry | volume = 16 | issue = 2 | pages = 120–62 | date = 2016-01-01 | pmid = 26349493 | doi=10.2174/1389557515666150909143737}}</ref> It is also involved in many oxidative stress diseases, cell signal transduction and cell proliferation process including cardiovascular disorders, [[sepsis]], and [[cancer]].<ref>{{cite journal | vauthors = Maccari R, Ottanà R | title = Targeting aldose reductase for the treatment of diabetes complications and inflammatory diseases: new insights and future directions | journal = Journal of Medicinal Chemistry | volume = 58 | issue = 5 | pages = 2047–67 | date = March 2015 | pmid = 25375908 | doi = 10.1021/jm500907a }}</ref>

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.<ref>{{cite journal | vauthors = Chang KC, Ponder J, Labarbera DV, Petrash JM | title = Aldose reductase inhibition prevents endotoxin-induced inflammatory responses in retinal microglia | journal = Investigative Ophthalmology & Visual Science | volume = 55 | issue = 5 | pages = 2853–61 | date = May 2014 | pmid = 24677107 | pmc = 4010364 | doi = 10.1167/iovs.13-13487 }}</ref> 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.<ref name="Grewal_2016" />

== Interactions ==

AKR1B1 has been found to interact with:

*[[ginsenoside 20(S)-Rh2]] <ref>{{cite journal | vauthors = Fatmawati S, Ersam T, Yu H, Zhang C, Jin F, Shimizu K | title = 20(S)-Ginsenoside Rh2 as aldose reductase inhibitor from Panax ginseng | journal = Bioorganic & Medicinal Chemistry Letters | volume = 24 | issue = 18 | pages = 4407–9 | date = September 2014 | pmid = 25152999 | doi = 10.1016/j.bmcl.2014.08.009 }}</ref>
*[[alkaloid]] <ref>{{cite journal | vauthors = Gupta S, Singh N, Jaggi AS | title = Alkaloids as aldose reductase inhibitors, with special reference to berberine | journal = Journal of Alternative and Complementary Medicine | volume = 20 | issue = 3 | pages = 195–205 | date = March 2014 | pmid = 24236461 | doi = 10.1089/acm.2013.0088 }}</ref>
*[[carboxylic acid derivatives]]<ref name="Grewal_2016" />
*[[spirohydantoins]]<ref name="Grewal_2016" />
*[[cyclic amides]]<ref name="Grewal_2016" />

== References ==
{{reflist|33em}}

== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Borhani DW, Harter TM, Petrash JM | title = The crystal structure of the aldose reductase.NADPH binary complex | journal = The Journal of Biological Chemistry | volume = 267 | issue = 34 | pages = 24841–7 | date = December 1992 | pmid = 1447221 | doi =  }}
* {{cite journal | vauthors = Wilson DK, Bohren KM, Gabbay KH, Quiocho FA | title = An unlikely sugar substrate site in the 1.65 A structure of the human aldose reductase holoenzyme implicated in diabetic complications | journal = Science | volume = 257 | issue = 5066 | pages = 81–4 | date = July 1992 | pmid = 1621098 | doi = 10.1126/science.1621098 }}
* {{cite journal | vauthors = Graham A, Heath P, Morten JE, Markham AF | title = The human aldose reductase gene maps to chromosome region 7q35 | journal = Human Genetics | volume = 86 | issue = 5 | pages = 509–14 | date = March 1991 | pmid = 1901827 | doi = 10.1007/BF00194644 }}
* {{cite journal | vauthors = Graham A, Brown L, Hedge PJ, Gammack AJ, Markham AF | title = Structure of the human aldose reductase gene | journal = The Journal of Biological Chemistry | volume = 266 | issue = 11 | pages = 6872–7 | date = April 1991 | pmid = 1901857 | doi =  }}
* {{cite journal | vauthors = Grundmann U, Bohn H, Obermeier R, Amann E | title = Cloning and prokaryotic expression of a biologically active human placental aldose reductase | journal = DNA and Cell Biology | volume = 9 | issue = 3 | pages = 149–57 | date = April 1990 | pmid = 2111143 | doi = 10.1089/dna.1990.9.149 }}
* {{cite journal | vauthors = Nishimura C, Matsuura Y, Kokai Y, Akera T, Carper D, Morjana N, Lyons C, Flynn TG | title = Cloning and expression of human aldose reductase | journal = The Journal of Biological Chemistry | volume = 265 | issue = 17 | pages = 9788–92 | date = June 1990 | pmid = 2112546 | doi =  }}
* {{cite journal | vauthors = Morjana NA, Lyons C, Flynn TG | title = Aldose reductase from human psoas muscle. Affinity labeling of an active site lysine by pyridoxal 5'-phosphate and pyridoxal 5'-diphospho-5'-adenosine | journal = The Journal of Biological Chemistry | volume = 264 | issue = 5 | pages = 2912–9 | date = February 1989 | pmid = 2492527 | doi =  }}
* {{cite journal | vauthors = Bohren KM, Bullock B, Wermuth B, Gabbay KH | title = The aldo-keto reductase superfamily. cDNAs and deduced amino acid sequences of human aldehyde and aldose reductases | journal = The Journal of Biological Chemistry | volume = 264 | issue = 16 | pages = 9547–51 | date = June 1989 | pmid = 2498333 | doi =  }}
* {{cite journal | vauthors = Chung S, LaMendola J | title = Cloning and sequence determination of human placental aldose reductase gene | journal = The Journal of Biological Chemistry | volume = 264 | issue = 25 | pages = 14775–7 | date = September 1989 | pmid = 2504709 | doi =  }}
* {{cite journal | vauthors = Graham A, Hedge PJ, Powell SJ, Riley J, Brown L, Gammack A, Carey F, Markham AF | title = Nucleotide sequence of cDNA for human aldose reductase | journal = Nucleic Acids Research | volume = 17 | issue = 20 | pages = 8368 | date = October 1989 | pmid = 2510130 | pmc = 334974 | doi = 10.1093/nar/17.20.8368 }}
* {{cite journal | vauthors = Akagi Y, Kador PF, Kuwabara T, Kinoshita JH | title = Aldose reductase localization in human retinal mural cells | journal = Investigative Ophthalmology & Visual Science | volume = 24 | issue = 11 | pages = 1516–9 | date = November 1983 | pmid = 6417042 | doi =  }}
* {{cite journal | vauthors = Ko BC, Lam KS, Wat NM, Chung SS | title = 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 | journal = Diabetes | volume = 44 | issue = 7 | pages = 727–32 | date = July 1995 | pmid = 7789640 | doi = 10.2337/diabetes.44.7.727 }}
* {{cite journal | vauthors = Wilson DK, Tarle I, Petrash JM, Quiocho FA | title = Refined 1.8 A structure of human aldose reductase complexed with the potent inhibitor zopolrestat | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 21 | pages = 9847–51 | date = November 1993 | pmid = 8234324 | pmc = 47669 | doi = 10.1073/pnas.90.21.9847 }}
* {{cite journal | vauthors = Tarle I, Borhani DW, Wilson DK, Quiocho FA, Petrash JM | title = Probing the active site of human aldose reductase. Site-directed mutagenesis of Asp-43, Tyr-48, Lys-77, and His-110 | journal = The Journal of Biological Chemistry | volume = 268 | issue = 34 | pages = 25687–93 | date = December 1993 | pmid = 8245005 | doi =  }}
* {{cite journal | vauthors = Robinson B, Hunsaker LA, Stangebye LA, Vander Jagt DL | title = Aldose and aldehyde reductases from human kidney cortex and medulla | journal = Biochimica et Biophysica Acta | volume = 1203 | issue = 2 | pages = 260–6 | date = December 1993 | pmid = 8268209 | doi = 10.1016/0167-4838(93)90092-6 }}
* {{cite journal | vauthors = Jaquinod M, Potier N, Klarskov K, Reymann JM, Sorokine O, Kieffer S, Barth P, Andriantomanga V, Biellmann JF, Van Dorsselaer A | title = Sequence of pig lens aldose reductase and electrospray mass spectrometry of non-covalent and covalent complexes | journal = European Journal of Biochemistry | volume = 218 | issue = 3 | pages = 893–903 | date = December 1993 | pmid = 8281941 | doi = 10.1111/j.1432-1033.1993.tb18445.x }}
* {{cite journal | vauthors = Liu SQ, Bhatnagar A, Ansari NH, Srivastava SK | title = Identification of the reactive cysteine residue in human placenta aldose reductase | journal = Biochimica et Biophysica Acta | volume = 1164 | issue = 3 | pages = 268–72 | date = August 1993 | pmid = 8343525 | doi = 10.1016/0167-4838(93)90258-S }}
* {{cite journal | vauthors = Nishimura C, Furue M, Ito T, Omori Y, Tanimoto T | title = Quantitative determination of human aldose reductase by enzyme-linked immunosorbent assay. Immunoassay of human aldose reductase | journal = Biochemical Pharmacology | volume = 46 | issue = 1 | pages = 21–8 | date = July 1993 | pmid = 8347133 | doi = 10.1016/0006-2952(93)90343-U }}
* {{cite journal | vauthors = Sato S, Lin LR, Reddy VN, Kador PF | title = Aldose reductase in human retinal pigment epithelial cells | journal = Experimental Eye Research | volume = 57 | issue = 2 | pages = 235–41 | date = August 1993 | pmid = 8405190 | doi = 10.1006/exer.1993.1119 }}
* {{cite journal | vauthors = Ferraretto A, Negri A, Giuliani A, De Grada L, Fuhrman Conti AM, Ronchi S | title = Aldose reductase is involved in long-term adaptation of EUE cells to hyperosmotic stress | journal = Biochimica et Biophysica Acta | volume = 1175 | issue = 3 | pages = 283–8 | date = February 1993 | pmid = 8435445 | doi = 10.1016/0167-4889(93)90218-E }}
{{refend}}

== External links ==
* {{UCSC gene info|AKR1B1}}
* {{UCSC gene info|AR}}

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[[Category:EC 1.1.1]]