Biology:Aldose reductase

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Short description: Enzyme
Aldose reductase
Aldose reductase 1us0.png
Ribbon diagram of human aldose reductase in complex with NADP+, citrate, and IDD594, a small molecule inhibitor. From PDB: 1us0​.
Identifiers
EC number1.1.1.21
CAS number9028-31-3
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum

In enzymology, aldose reductase (or aldehyde reductase) (EC 1.1.1.21) is a cytosolic NADPH-dependent oxidoreductase that 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.[1]

Reactions

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.[1]

glucose + NADPH + H+ [math]\displaystyle{ \rightleftharpoons }[/math] sorbitol + NADP+

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.[2] Nevertheless, aldose reductase can catalyze the reduction of galactose to galactitol

galactose + NADPH + H+ [math]\displaystyle{ \rightleftharpoons }[/math] galactitol + NADP+
pathway alt text
Polyol pathway scheme depicting both the NADPH-dependent reduction step catalyzed by aldose reductase and the NAD+-induced oxidation catalyzed by sorbitol dehydrogenase

Function

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 ATP:

  • Seminal vesicles: Fructose produced from sorbitol is used by the sperm cells.
  • Liver: Fructose produced from sorbitol can be used as an energy source for glycolysis and glyconeogenesis.

Aldose reductase is also present in the lens, retina, Schwann cells of peripheral nerves, placenta and red blood cells.[citation needed]

In Drosophila, CG6084 encoded a highly conserved protein of human Aldo-keto reductase 1B. dAKR1B in hemocytes, is necessary and sufficient for the increasement of plasma sugar alcohols after gut infection. Increased sorbitol subsequently activated Metalloprotease 2, which cleaves PGRP-LC to activate systemic immune response in fat bodies. Thus, aldose reductase provides a critical metabolic checkpoint in the global inflammatory response.[3]

Enzyme structure

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.[4] Adjacent strands are connected by eight peripheral α-helical segments running anti-parallel to the β sheet.[5] The catalytic active site situated in the barrel core.[5][6] 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.[1]

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.
pathway alt text
Depiction of NADPH in extended confirmation and hydrogen bonded to the residues physically near the active site of the enzyme.
Role of aldehyde reductase (shown in yellow box) in norepinephrine degradation, contributing in the creation of MHPG, a minor catecholamine metabolite.[7]
Role of aldehyde dehydrogenase (shown in red box) in norepinephrine.[7]

Enzyme mechanism

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+ → E•NADP+) in order to release NADP+.[8] Kinetic studies have shown that reorientation of this loop to permit release of NADP+ appears to represent the rate-limiting step in the direction of aldehyde reduction.[9][10][11] 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).[11]

The hydride that is transferred from NADP+ 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.[5][12][13] 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.[5]

Role in diabetes

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), kidney, and the myelin sheath–tissues that are often involved in diabetic complications.[14] 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.[15][16] 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.[17] 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 inhibitors 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, risarestat, sorbinil, and berberine[18] are currently in clinical trials.[19]

See also

References

  1. ↑ 1.0 1.1 1.2 Petrash JM (April 2004). "All in the family: aldose reductase and closely related aldo-keto reductases". Cell. Mol. Life Sci. 61 (7–8): 737–49. doi:10.1007/s00018-003-3402-3. PMID 15094999. 
  2. ↑ "Lens polyol dehydrogenase". Exp. Eye Res. 16 (2): 95–104. June 1973. doi:10.1016/0014-4835(73)90304-7. PMID 4352688. 
  3. ↑ "Sugar Alcohols of Polyol Pathway Serve as Alarmins to Mediate Local-Systemic Innate Immune Communication in Drosophila". Cell Host & Microbe 26 (2): 240–251. August 2019. doi:10.1016/j.chom.2019.07.001. PMID 31350199. 
  4. ↑ "Characterization of the human aldehyde reductase gene and promoter". Genomics 60 (2): 188–98. September 1999. doi:10.1006/geno.1999.5915. PMID 10486210. 
  5. ↑ 5.0 5.1 5.2 5.3 "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. doi:10.1126/science.1621098. PMID 1621098. 
  6. ↑ "Novel NADPH-binding domain revealed by the crystal structure of aldose reductase". Nature 355 (6359): 469–72. January 1992. doi:10.1038/355469a0. PMID 1734286. Bibcode: 1992Natur.355..469R. 
  7. ↑ 7.0 7.1 Figure 11-4 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007). Rang & Dale's pharmacology. Edinburgh: Churchill Livingstone. ISBN 978-0-443-06911-6. 
  8. ↑ "Kinetic and spectroscopic evidence for active site inhibition of human aldose reductase". Biochemistry 35 (34): 11196–202. August 1996. doi:10.1021/bi9608121. PMID 8780524. 
  9. ↑ "Mechanistic basis for nonlinear kinetics of aldehyde reduction catalyzed by aldose reductase". Biochemistry 29 (42): 9947–55. October 1990. doi:10.1021/bi00494a027. PMID 2125486. 
  10. ↑ "Studies on pig muscle aldose reductase. Kinetic mechanism and evidence for a slow conformational change upon coenzyme binding". J. Biol. Chem. 267 (10): 6510–7. April 1992. doi:10.1016/S0021-9258(19)50457-4. PMID 1551865. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=1551865. Retrieved 2010-05-18. 
  11. ↑ 11.0 11.1 "Human aldose reductase: rate constants for a mechanism including interconversion of ternary complexes by recombinant wild-type enzyme". Biochemistry 34 (44): 14356–65. November 1995. doi:10.1021/bi00044a012. PMID 7578039. 
  12. ↑ "Probing the active site of human aldose reductase. Site-directed mutagenesis of Asp-43, Tyr-48, Lys-77, and His-110". J. Biol. Chem. 268 (34): 25687–93. December 1993. doi:10.1016/S0021-9258(19)74444-5. PMID 8245005. http://www.jbc.org/cgi/pmidlookup?view=long&pmid=8245005. Retrieved 2010-05-18. 
  13. ↑ "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". Biochemistry 33 (8): 2021–32. March 1994. doi:10.1021/bi00174a007. PMID 8117659. 
  14. ↑ "From hyperglycemia to diabetic kidney disease: the role of metabolic, hemodynamic, intracellular factors and growth factors/cytokines". Endocr. Rev. 25 (6): 971–1010. December 2004. doi:10.1210/er.2003-0018. PMID 15583025. http://edrv.endojournals.org/cgi/pmidlookup?view=long&pmid=15583025. Retrieved 2010-05-18. 
  15. ↑ "Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes". Science 151 (3707): 209–10. January 1966. doi:10.1126/science.151.3707.209. PMID 5907911. Bibcode: 1966Sci...151..209G. 
  16. ↑ "Methylglyoxal and the polyol pathway. Three-carbon compounds are substrates for sheep liver sorbitol dehydrogenase". FEBS Lett. 330 (1): 31–5. September 1993. doi:10.1016/0014-5793(93)80913-F. PMID 8370454. 
  17. ↑ "The effect of high glucose and oxidative stress on lens metabolism, aldose reductase, and senile cataractogenesis". Metab. Clin. Exp. 35 (4 Suppl 1): 10–4. April 1986. doi:10.1016/0026-0495(86)90180-0. PMID 3083198. 
  18. ↑ "The anti-necrosis role of hypoxic preconditioning after acute anoxia is mediated by aldose reductase and sorbitol pathway in PC12 cells". Cell Stress & Chaperones 15 (4): 387–94. November 2009. doi:10.1007/s12192-009-0153-6. PMID 19902381. 
  19. ↑ "Aldose reductase inhibitors in the treatment of diabetic peripheral neuropathy: a review". J. Diabetes Complicat. 24 (5): 354–60. September 2009. doi:10.1016/j.jdiacomp.2009.07.005. PMID 19748287. 

Further reading

  • Denise R., PhD. Ferrier (2005). Lippincott's Illustrated Reviews: Biochemistry (Lippincott's Illustrated Reviews). Hagerstown, Maryland: Lippincott Williams & Wilkins. p. 319. ISBN 0-7817-2265-9. 
  • "Purification and properties of calf liver aldose reductase". Biochim. Biophys. Acta 370 (2): 358–68. December 1974. doi:10.1016/0005-2744(74)90097-7. PMID 4216364. 
  • "Affinity purification and properties of porcine brain aldose reductase". Biochim. Biophys. Acta 567 (2): 278–86. April 1979. doi:10.1016/0005-2744(79)90113-x. PMID 36151. 



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