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[http://en.wikipedia.org/wiki/Aldose_reductase Wikipedia] | [http://en.wikipedia.org/wiki/Aldose_reductase Wikipedia] | ||
==Introduction== | ==Introduction== | ||
| - | Aldose reductase is an oxidoreductase/dehydrogenase enzyme.<ref name="wikipedia"> Wikipedia. Aldose Reductase. http://en.wikipedia.org/wiki/Aldose_reductase </ref> It reduces aldehydes and carbonyl, including monosaccharides to their corresponding alcohol products using NADPH as a cofactor.<ref name="wikipedia"/><ref name="Steuber"> PMID 17368668 </ref> Aldose reductase is most well known in the first step of the polyol pathway of glucose metabolism.<ref name=" | + | Aldose reductase is an oxidoreductase/dehydrogenase enzyme.<ref name="wikipedia"> Wikipedia. Aldose Reductase. http://en.wikipedia.org/wiki/Aldose_reductase </ref> It reduces aldehydes and carbonyl, including monosaccharides to their corresponding alcohol products using NADPH as a cofactor.<ref name="wikipedia"/><ref name="Steuber"> PMID 17368668 </ref> Aldose reductase is most well known in the first step of the polyol pathway of glucose metabolism.<ref name="review"> PMID 15094999 </ref><ref name="Steuber"/>Aldose reductase is also able to reduce galactose to galactitol.<ref name="review"/> |
==Polyol Pathway and Diabetes== | ==Polyol Pathway and Diabetes== | ||
| - | The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.<ref name="wikipedia"/> | + | The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.<ref name="review"/><ref name="wikipedia"/><ref name="Steuber"/> The first step of the pathway is the production of sorbitol from glucose, catalyzed by aldose reductase and using NADPH as a reducing cofactor.<ref name="review"/><ref name="Steuber"/> The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase using NAD+.<ref name="review"/><ref name="Steuber"/> Under normal blood glucose levels most glucose is metabolized through glycolysis or the pentose phosphate pathway while only a small amount of glucose is metabolized through the polyol pathway.<ref name="review"/> Under the hyperglycemic conditions of diabetes the flux of glucose through the polyol pathway is increased.<ref name="review"/><ref name="Steuber"/> This causes osmotic and oxidative stress, which can cause pathological interferences with cytokine signalling, regulation of apoptosis, and activation of kinase cascades.<ref name="Steuber"/> For example, under increased glucose flux through the polyol pathway protein kinase C activivty increases, which causes smooth muscle cell proliferation of blood vessels in agreement with atherosclerosis.<ref name="Steuber"/> This explains estimates that 75-80% of adults with diabetes die from complications of atherosclerosis.<ref name="Steuber"/> Aldose reductase is located in the cornea, retina, lens, kidneys, and myelin sheath.<ref name="wikipedia"/> This correlates with long-term complications such as retinopathy, nephropathy, neuropathy, cataracts, and angiopathy.<ref name="Steuber"/> Aldose reductase inhibitors are possible beneficial treatment options for diabetes.<ref name="Steuber"/> |
| - | <ref name="Steuber"/> The first step of the pathway is the production of sorbitol from glucose, catalyzed by aldose reductase and using NADPH as a reducing cofactor.<ref name=" | + | |
==Structure== | ==Structure== | ||
| - | Aldose reductase is a 36kDa aldo-keto reductase<ref name="Steuber"/> | + | Aldose reductase is a 36kDa aldo-keto reductase made of a single 315 amino acid residue polypeptide chain.<ref name="Steuber"/><ref name="review"/> It has a (β/α)8-TIM-barrel structural motif made of 8 parallel β strands connected to 8 peripheral α helices running anti-parallel to the β strands.<ref name="wikipedia"/> Including the β-strands and α-helices of the TIM barrel, aldose reductase has a total of 10 helices and 13 β-strands. The catalytic active site is located at the C-terminal loop of the enzyme<ref name="Steuber"/> in the barrel core.<ref name="wikipedia"/> The NADPH cofactor is situated at the top of the barrel with the nicotinamide ring projecting down the center of the barrel and the pyrophosphate straddling the lip of the barrel.<ref name="wikipedia"/> The substrate binding pocket is deeply buried and made of residues that are most likely involved in the catalytic reaction (involving residues Tyr48, Lys77, His110).<ref name="Steuber"/> The nicotinamide moiety of NADP+ and Trp111 interact with the head group of most ligands.<ref name="Steuber"/> Hydrophobic contacts can be formed by the side-chains of Trp20, Val47, Trp79, and Trp219.<ref name="Steuber"/> |
==Mechanism== | ==Mechanism== | ||
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Aldose Reductase (2IKH)
|
Introduction
Aldose reductase is an oxidoreductase/dehydrogenase enzyme.[1] It reduces aldehydes and carbonyl, including monosaccharides to their corresponding alcohol products using NADPH as a cofactor.[1][2] Aldose reductase is most well known in the first step of the polyol pathway of glucose metabolism.[3][2]Aldose reductase is also able to reduce galactose to galactitol.[3]
Polyol Pathway and Diabetes
The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.[3][1][2] The first step of the pathway is the production of sorbitol from glucose, catalyzed by aldose reductase and using NADPH as a reducing cofactor.[3][2] The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase using NAD+.[3][2] Under normal blood glucose levels most glucose is metabolized through glycolysis or the pentose phosphate pathway while only a small amount of glucose is metabolized through the polyol pathway.[3] Under the hyperglycemic conditions of diabetes the flux of glucose through the polyol pathway is increased.[3][2] This causes osmotic and oxidative stress, which can cause pathological interferences with cytokine signalling, regulation of apoptosis, and activation of kinase cascades.[2] For example, under increased glucose flux through the polyol pathway protein kinase C activivty increases, which causes smooth muscle cell proliferation of blood vessels in agreement with atherosclerosis.[2] This explains estimates that 75-80% of adults with diabetes die from complications of atherosclerosis.[2] Aldose reductase is located in the cornea, retina, lens, kidneys, and myelin sheath.[1] This correlates with long-term complications such as retinopathy, nephropathy, neuropathy, cataracts, and angiopathy.[2] Aldose reductase inhibitors are possible beneficial treatment options for diabetes.[2]
Structure
Aldose reductase is a 36kDa aldo-keto reductase made of a single 315 amino acid residue polypeptide chain.[2][3] It has a (β/α)8-TIM-barrel structural motif made of 8 parallel β strands connected to 8 peripheral α helices running anti-parallel to the β strands.[1] Including the β-strands and α-helices of the TIM barrel, aldose reductase has a total of 10 helices and 13 β-strands. The catalytic active site is located at the C-terminal loop of the enzyme[2] in the barrel core.[1] The NADPH cofactor is situated at the top of the barrel with the nicotinamide ring projecting down the center of the barrel and the pyrophosphate straddling the lip of the barrel.[1] The substrate binding pocket is deeply buried and made of residues that are most likely involved in the catalytic reaction (involving residues Tyr48, Lys77, His110).[2] The nicotinamide moiety of NADP+ and Trp111 interact with the head group of most ligands.[2] Hydrophobic contacts can be formed by the side-chains of Trp20, Val47, Trp79, and Trp219.[2]
Mechanism
The exact mechanism of the operation of the enzyme is under discussion.[2] NADPH donates a hydride ion to the carbonyl carbon of the aldehyde.[1][2] The hydride transferred from NADPH to glucose comes from C-4 of the nicotinamide ring at the base of the hydrophobic cavity.[1] Most likely then the transfer of a proton from one of the neighbouring acidic residues to the intermediately formed substrate ion occurs.[2] Tyr48, His110, and Cys298 are all within a proper distance of C-4 to be potential proton donors.[1] Evolutionary, thermodynamic, and molecular modeling evidence predicted that Tyr48 was the proton donor.[1] Mutagenesis studies confirmed it was Tyr48.[1] The NADPH binds to the polypeptide first, followed by the substrate.[1] The binding of NADPH induces a conformational change that involves a hinge-like movement of the surface loop (residues 213-217) so it covers part of the NADPH like a safety belt.[1] After the reaction occurs and the alcohol product has been released another conformational change occurs to release the NADP+.[1] Kinetic studies have shown that the reorientation of the loop to permit the release of the NADP+ may be the rate-limiting step.[1] Thus, disturbing interactions that stabilize the coenzyme binding can have dramatic effects on the maximum rate of the reaction.[1] Hydrogen-bonding interaction between the phenolic hydroxyl group of Tyr48 and the ammonium side chain of Lys77 are thought to help facilitate hydride transfer.[1]
References
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 Wikipedia. Aldose Reductase. http://en.wikipedia.org/wiki/Aldose_reductase
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 Steuber H, Heine A, Klebe G. Structural and thermodynamic study on aldose reductase: nitro-substituted inhibitors with strong enthalpic binding contribution. J Mol Biol. 2007 May 4;368(3):618-38. Epub 2006 Dec 15. PMID:17368668 doi:10.1016/j.jmb.2006.12.004
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 Petrash JM. All in the family: aldose reductase and closely related aldo-keto reductases. Cell Mol Life Sci. 2004 Apr;61(7-8):737-49. PMID:15094999 doi:10.1007/s00018-003-3402-3
