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<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="wikipedia"/><ref name="Steuber"/> The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase, which is NAD+ dependent.<ref name="wikipedia"/><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="wikipedia"/> Under the hyperglycemic conditions of diabetes the flux of glucose through the polyol pathway is increased.<ref name="wikipedia"/><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="wikipedia"/><ref name="Steuber"/> The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase, which is NAD+ dependent.<ref name="wikipedia"/><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="wikipedia"/> Under the hyperglycemic conditions of diabetes the flux of glucose through the polyol pathway is increased.<ref name="wikipedia"/><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"/> | ||
==Structure== | ==Structure== | ||
| - | Aldose reductase is a 36kDa aldo-keto reductase | + | Aldose reductase is a 36kDa aldo-keto reductase<ref name="Steuber"/> made of 315 amino acid residues.<ref name="wikipedia"/> 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"/> The catalytic active site is located 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"/> |
==References== | ==References== | ||
<references/> | <references/> | ||
Revision as of 07:03, 13 March 2011
| This Sandbox is Reserved from January 10, 2010, through April 10, 2011 for use in BCMB 307-Proteins course taught by Andrea Gorrell at the University of Northern British Columbia, Prince George, BC, Canada. |
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Aldose Reductase (2IKH)
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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.[1][2]
Sub Title
Sub Sub Title
Polyol Pathway and Diabetes
The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.[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.[1][2] The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase, which is NAD+ dependent.[1][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.[1] Under the hyperglycemic conditions of diabetes the flux of glucose through the polyol pathway is increased.[1][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[2] made of 315 amino acid residues.[1] 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] The catalytic active site is located 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]
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 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 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
