Sandbox Reserved 339

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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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Contents

Aldose Reductase (2IKH)

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Wikipedia

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]

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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 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]

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Wikipedia. Aldose Reductase. http://en.wikipedia.org/wiki/Aldose_reductase
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 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
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