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| {{enzyme
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| | Name = Aldose reductase
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| | EC_number = 1.1.1.21
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| | CAS_number = 9028-31-3
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| | IUBMB_EC_number = 1/1/1/21
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| | GO_code =
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| | image = Aldose reductase 1us0.png
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| | width =
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| | caption = [[Ribbon diagram]] of human aldose reductase in complex with [[nicotinamide adenine dinucleotide phosphate|NADP<sup>+</sup>]], [[citrate]], and IDD594, a small molecule [[enzyme inhibitor|inhibitor]]. From {{PDB|1us0}}.
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| In [[enzymology]], '''aldose reductase''' (or '''aldehyde reductase''') ({{EC number|1.1.1.21}}) is an [[NADPH]]-dependent [[oxidoreductase]] that [[catalysis|catalyzes]] the reduction of a variety of aldehydes and carbonyls, including monosaccharides. It is primarily known for catalyzing the reduction of [[glucose]] to [[sorbitol]], the first step in [[polyol pathway]] of glucose metabolism.<ref name="pmid15094999">{{cite journal | author = Petrash JM | title = All in the family: aldose reductase and closely related aldo-keto reductases | journal = Cell. Mol. Life Sci. | volume = 61 | issue = 7–8 | pages = 737–49 |date=April 2004 | pmid = 15094999 | doi = 10.1007/s00018-003-3402-3 | url = }}</ref>
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| ==Reactions==
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| Aldose reductase catalyzes the NADPH-dependent conversion of [[glucose]] to [[sorbitol]], the first step in [[polyol pathway]] of glucose metabolism. The second and last step in the pathway is catalyzed by [[sorbitol dehydrogenase]], which catalyzes the NAD-linked oxidation of sorbitol to fructose. Thus, the polyol pathway results in conversion of glucose to fructose with stoichiometric utilization of NADPH and production of NADH.<ref name="pmid15094999"/>
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| ;[[glucose]] + NADPH + H<sup>+</sup> <math>\rightleftharpoons</math> [[sorbitol]] + NADP<sup>+</sup>
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| Galactose is also a substrate for the polyol pathway, but the corresponding keto sugar is not produced because sorbitol dehydrogenase is incapable of oxidizing galactitol.<ref name="pmid 4352688">{{cite journal |author=Jedziniak JA, Yates EM, Kinoshita JH |title=Lens polyol dehydrogenase |journal=[[Exp. Eye Res.]] |volume=16 |issue=2 |pages=95–104 |date=June 1973 |pmid=4352688 |doi= 10.1016/0014-4835(73)90304-7|url=http://linkinghub.elsevier.com/retrieve/pii/0014-4835(73)90304-7 |accessdate=2010-05-18}}</ref><ref name="pmid 4352688"/> Nevertheless, aldose reductase can catalyze the reduction of galactose to galactitol
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| ;[[galactose]] + NADPH + H<sup>+</sup> <math>\rightleftharpoons</math> [[galactitol]] + NADP<sup>+</sup>
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| [[File:PolyolPathway.png|thumb|alt=pathway alt text|Polyol pathway scheme depicting both the NADPH-dependent reduction step catalyzed by aldose reductase and the NAD<sup>+</sup>-induced oxidation catalyzed by sorbitol dehydrogenase]]
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| ==Function==
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| The aldose reductase reaction, in particular the sorbitol produced, is important for the function of various organs in the body. For example, it is generally used as the first step in a synthesis of [[fructose]] from glucose; the second step is the oxidation of sorbitol to fructose catalyzed by [[sorbitol dehydrogenase]]. The main pathway from glucose to fructose ([[glycolysis]]) involves [[phosphorylation]] of glucose by [[hexokinase]] to form [[glucose 6-phosphate]], followed by isomerization to [[fructose 6-phosphate]] and [[hydrolysis]] of the phosphate, but the sorbitol pathway is useful because it does not require the input of [[energy]] in the form of [[adenosine triphosphate|ATP]]:
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| *[[Seminal vesicle]]s: Fructose produced from sorbitol is used by the [[Spermatozoon|sperm cells]].
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| *[[Liver]]: Fructose produced from sorbitol can be used as an energy source for glycolysis and [[glyconeogenesis]].
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| Aldose reductase is also present in the [[lens (anatomy)|lens]], [[retina]], [[Schwann cells]] of peripheral nerves, [[placenta]] and [[red blood cells]].{{citation needed|date=December 2012}}
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| ==Enzyme Structure==
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| Aldose reductase may be considered a prototypical enzyme of the aldo-keto reductase enzyme superfamily. The enzyme comprises 315 amino acid residues and folds into a β/α-barrel structural motif composed of eight parallel β strands.<ref name="pmid10486210">{{cite journal |author=Barski OA, Gabbay KH, Bohren KM |title=Characterization of the human aldehyde reductase gene and promoter |journal=[[Genomics (journal)|Genomics]] |volume=60 |issue=2 |pages=188–98 |date=September 1999 |pmid=10486210 |doi=10.1006/geno.1999.5915 |url=http://linkinghub.elsevier.com/retrieve/pii/S0888-7543(99)95915-3 |accessdate=2010-05-18}}</ref> Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet.<ref name="pmid1621098">{{cite journal |author=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 (journal)|Science]] |volume=257 |issue=5066 |pages=81–4 |date=July 1992 |pmid=1621098 |doi= 10.1126/science.1621098|url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=1621098 |accessdate=2010-05-18}}</ref> The catalytic active site situated in the barrel core.<ref name="pmid1621098"/><ref name="pmid1734286">{{cite journal |author=Rondeau JM, Tête-Favier F, Podjarny A, ''et al.'' |title=Novel NADPH-binding domain revealed by the crystal structure of aldose reductase |journal=[[Nature (journal)|Nature]] |volume=355 |issue=6359 |pages=469–72 |date=January 1992 |pmid=1734286 |doi=10.1038/355469a0 |accessdate=2010-05-18}}</ref> The NADPH cofactor is situated at the top of the β/α barrel, with the nicotinamide ring projects down in the center of the barrel and pyrophosphate straddling the barrel lip.<ref name="pmid15094999">{{cite journal |author=Petrash JM |title=All in the family: aldose reductase and closely related aldo-keto reductases |journal=[[Cell. Mol. Life Sci.]] |volume=61 |issue=7-8 |pages=737–49 |date=April 2004 |isbn=0001800334023 {{Please check ISBN|reason=Check digit (3) does not correspond to calculated figure.}} {{Please check ISBN|reason=13 digit ISBN should start with 978 or 979.}} |pmid=15094999 |doi=10.1007/s00018-003-3402-3 |accessdate=2010-05-18}}</ref>
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| [[File:FinalMechanism3.png|thumb|alt=pathway alt text|Mechanism of NADPH-dependent conversion of glucose to sorbitol. Note the hydride transfer from NADPH to the carbonyl carbon of the aldose.]]
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| [[File:NADPHHydrogenbonded.png|thumb|alt=pathway alt text|Depiction of NADPH in extended confirmation and hydrogen bonded to the residues physically near the active site of the enzyme.]]
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| [[File:Noradrenaline breakdown.svg|thumb|350px|Role of aldehyde reductase (shown in yellow box) in [[norepinephrine]] degradation, contributing in the creation of [[3-Methoxy-4-hydroxyphenylglycol|MHPG]], a minor catecholamine metabolite.<ref name=Rang&Dale6th-11-4>Figure 11-4 in: {{cite book |author=Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. |title=Rang & Dale's pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2007 |pages= |isbn=0-443-06911-5 |oclc= |doi= |accessdate=}}</ref>]][[File:Noradrenaline breakdown.svg|thumb|350px|Role of aldehyde dehydrogenase (shown in red box) in [[norepinephrine]].<ref name="Rang&Dale6th-11-4"/>]]
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| ==Enzyme Mechanism==
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| The [[reaction mechanism]] of aldose reductase in the direction of aldehyde reduction follows a sequential ordered path where NADPH binds, followed by the substrate. Binding of NADPH induces a conformational change (Enzyme•NADPH –> Enzyme*•NADPH) that involves hinge-like movement of a surface loop (residues 213-217) so as to cover a portion of the NADPH in a manner similar to that of a safety belt. The alcohol product is formed via a transfer of the pro-R hydride of NADPH to the re face of the substrate's carbonyl carbon. Following release of the alcohol product, another conformational change occurs (E*•NADP<sup>+</sup> –> E•NADP<sup>+</sup>) in order to release NADP<sup>+</sup>.<ref name="pmid8780524">{{cite journal |author=Nakano T, Petrash JM |title=Kinetic and spectroscopic evidence for active site inhibition of human aldose reductase |journal=[[Biochemistry (journal)|Biochemistry]] |volume=35 |issue=34 |pages=11196–202 |date=August 1996 |pmid=8780524 |doi=10.1021/bi9608121 |accessdate=2010-05-18}}</ref> Kinetic studies have shown that reorientation of this loop to permit release of NADP<sup>+</sup> appears to represent the rate-limiting step in the direction of aldehyde reduction.<ref name="pmid2125486">{{cite journal |author=Grimshaw CE, Shahbaz M, Putney CG |title=Mechanistic basis for nonlinear kinetics of aldehyde reduction catalyzed by aldose reductase |journal=[[Biochemistry (journal)|Biochemistry]] |volume=29 |issue=42 |pages=9947–55 |date=October 1990 |pmid=2125486 |doi= 10.1021/bi00494a027|url= |accessdate=2010-05-18}}</ref><ref name="pmid1551865">{{cite journal |author=Kubiseski TJ, Hyndman DJ, Morjana NA, Flynn TG |title=Studies on pig muscle aldose reductase. Kinetic mechanism and evidence for a slow conformational change upon coenzyme binding |journal=[[J. Biol. Chem.]] |volume=267 |issue=10 |pages=6510–7 |date=April 1992 |pmid=1551865 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1551865 |accessdate=2010-05-18}}</ref><ref name="pmid7578039">{{cite journal |author=Grimshaw CE, Bohren KM, Lai CJ, Gabbay KH |title=Human aldose reductase: rate constants for a mechanism including interconversion of ternary complexes by recombinant wild-type enzyme |journal=[[Biochemistry (journal)|Biochemistry]] |volume=34 |issue=44 |pages=14356–65 |date=November 1995 |pmid=7578039 |doi= 10.1021/bi00044a012|url= |accessdate=2010-05-18}}</ref> As the rate of coenzyme release limits the catalytic rate, it can be seen that perturbation of interactions that stabilize coenzyme binding can have dramatic effects on the maximum velocity (Vmax).<ref name="pmid7578039"/>
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| The hydride that is transferred from NADP<sup>+</sup> to glucose comes from C-4 of the [[nicotinamide]] ring at the base of the hydrophobic cavity. Thus, the position of this carbon defines the enzyme's active site. There exist three residues in the enzyme within a suitable distance of the C-4 that could be potential proton donors: Tyr-48, His-110 and Cys-298. Evolutionary, thermodynamic and molecular modeling evidence predicted Tyr-48 as the proton donor. This prediction was confirmed the results of mutagenesis studies.<ref name="pmid1621098"/><ref name="pmid8245005">{{cite journal |author=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=[[J. Biol. Chem.]] |volume=268 |issue=34 |pages=25687–93 |date=December 1993 |pmid=8245005 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8245005 |accessdate=2010-05-18}}</ref><ref name="pmid8117659">{{cite journal |author=Bohren KM, Grimshaw CE, Lai CJ, ''et al.'' |title=Tyrosine-48 is the proton donor and histidine-110 directs substrate stereochemical selectivity in the reduction reaction of human aldose reductase: enzyme kinetics and crystal structure of the Y48H mutant enzyme |journal=[[Biochemistry (journal)|Biochemistry]] |volume=33 |issue=8 |pages=2021–32 |date=March 1994 |pmid=8117659 |doi= 10.1021/bi00174a007|url= |accessdate=2010-05-18}}</ref> Thus, a [hydrogen-bonding] interaction between the phenolic hydroxyl group of Tyr-48 and the ammonium side chain of Lys-77 is thought to help to facilitate hydride transfer.<ref name="pmid1621098"/>
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| ==Role in diabetes==
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| [[Diabetes mellitus]] is recognized as a leading cause of new cases of blindness, and is associated with increased risk for painful neuropathy, heart disease and kidney failure. Many theories have been advanced to explain mechanisms leading to diabetic complications, including stimulation of glucose metabolism by the polyol pathway. Additionally, the enzyme is located in the eye ([[cornea]], [[retina]], [[Lens (anatomy)|lens]]), [[kidney]], and the [[myelin sheath]]–tissues that are often involved in diabetic complications.<ref name="pmid15583025">{{cite journal |author=Schrijvers BF, De Vriese AS, Flyvbjerg A |title=From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines |journal=[[Endocr. Rev.]] |volume=25 |issue=6 |pages=971–1010 |date=December 2004 |pmid=15583025 |doi=10.1210/er.2003-0018 |url=http://edrv.endojournals.org/cgi/pmidlookup?view=long&pmid=15583025 |accessdate=2010-05-18}}</ref> Under normal glycemic conditions, only a small fraction of glucose is metabolized through the polyol pathway, as the majority is phosphorylated by hexokinase, and the resulting product, glucose-6-phosphate, is utilized as a substrate for glycolysis or pentose phosphate metabolism.<ref name="pmid5907911">{{cite journal |author=Gabbay KH, Merola LO, Field RA |title=Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes |journal=[[Science (journal)|Science]] |volume=151 |issue=3707 |pages=209–10 |date=January 1966 |pmid=5907911 |doi= 10.1126/science.151.3707.209|url=http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=5907911 |accessdate=2010-05-18}}</ref><ref name="pmid8370454">{{cite journal |author=Lindstad RI, McKinley-McKee JS |title=Methylglyoxal and the polyol pathway. Three-carbon compounds are substrates for sheep liver sorbitol dehydrogenase |journal=[[FEBS Lett.]] |volume=330 |issue=1 |pages=31–5 |date=September 1993 |pmid=8370454 |doi= 10.1016/0014-5793(93)80913-F|url=http://linkinghub.elsevier.com/retrieve/pii/0014-5793(93)80913-F |accessdate=2010-05-18}}</ref> However, in response to the chronic [[hyperglycemia]] found in diabetics, glucose flux through the polyol pathway is significantly increased. Up to 33% of total glucose utilization in some tissues can be through the polyol pathway.<ref name="pmid3083198">{{cite journal |author=Cheng HM, González RG |title=The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis |journal=[[Metab. Clin. Exp.]] |volume=35 |issue=4 Suppl 1 |pages=10–4 |date=April 1986 |pmid=3083198 |doi= 10.1016/0026-0495(86)90180-0|url= |accessdate=2010-05-18}}</ref>
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| Glucose concentrations are often elevated in [[diabetics]] and aldose reductase has long been believed to be responsible for diabetic complications involving a number of organs. Many [[aldose reductase inhibitor]]s have been developed as drug candidates but virtually all have failed although some such as [[epalrestat]] are commercially available in several countries. Additional reductase inhibitors such as [[ranirestat]], [[ponalrestat]], [[rinalrestat]], [[risarestat]], [[sorbinil]], and [[berberine]]<ref name="pmid19902381">{{cite journal | author = Wu LY, Ma ZM, Fan XL, Zhao T, Liu ZH, Huang X, Li MM, Xiong L, Zhang K, Zhu LL, Fan M | title = The anti-necrosis role of hypoxic preconditioning after acute anoxia is mediated by aldose reductase and sorbitol pathway in PC12 cells | journal = Cell Stress Chaperones | volume = 15| issue = 4| pages = 387–94|date=November 2009 | pmid = 19902381 | doi = 10.1007/s12192-009-0153-6 | url = | issn = | pmc=3082650}}</ref> are currently in clinical trials.<ref name="pmid19748287">{{cite journal | author = Schemmel KE, Padiyara RS, D'Souza JJ | title = Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review | journal = J. Diabetes Complicat. | volume = 24| issue = 5| pages = 354–60|date=September 2009 | pmid = 19748287 | doi = 10.1016/j.jdiacomp.2009.07.005 | url = }}</ref>
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| == See also ==
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| * [[AKR1B1]]
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| * [[Aldo-keto reductase]]
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| ==References==
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| {{reflist}}
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| ==Further reading==
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| {{refbegin}}
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| * {{cite book |author=Denise R., PhD. Ferrier |title=Lippincott's Illustrated Reviews: Biochemistry (Lippincott's Illustrated Reviews) |publisher=Lippincott Williams & Wilkins |location=Hagerstown, Maryland |year=2005 |isbn=0-7817-2265-9 |oclc= |doi= |page=319}}
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| * {{cite journal | author = Attwood MA, Doughty CC | title = Purification and properties of calf liver aldose reductase | journal = Biochim. Biophys. Acta | volume = 370 | issue = 2 | pages = 358–68 |date=December 1974 | pmid = 4216364 | doi = | url = }}
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| * {{cite journal | author = Boghosian RA, McGuinness ET | title = Affinity purification and properties of porcine brain aldose reductase | journal = Biochim. Biophys. Acta | volume = 567 | issue = 2 | pages = 278–86 |date=April 1979 | pmid = 36151 | doi = | url = }}
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| {{refend}}
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| {{Alcohol oxidoreductases}}
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| {{Fructose and galactose metabolism}}
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| [[Category:EC 1.1.1]]
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| [[Category:NADPH-dependent enzymes]]
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| [[Category:Enzymes of known structure]]
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Hello and welcome. My title is Numbers Wunder. I am a meter reader but I strategy on altering it. One of the issues he loves most is ice skating but he is struggling to discover time for it. North Dakota is her beginning location but she will have to move 1 working day or an additional.
my blog: sex-porn-tube.ch