Sandbox Reserved 339: Difference between revisions
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The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.<ref name="Steuber"/><ref name="review"/><ref name="wikipedia"/> 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="Steuber"/><ref name="review"/> The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase using NAD+.<ref name="Steuber"/><ref name="review"/> 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="Steuber"/><ref name="review"/> 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"/> | The polyol pathway involves the synthesis of fructose from glucose, but does not require energy from ATP like glycolysis does.<ref name="Steuber"/><ref name="review"/><ref name="wikipedia"/> 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="Steuber"/><ref name="review"/> The second step in the pathway is the production of fructose from sorbitol, catalyzed by sorbitol dehydrogenase using NAD+.<ref name="Steuber"/><ref name="review"/> 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="Steuber"/><ref name="review"/> 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 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="Steuber"/><ref name="review"/> 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 deeply buried inside the barrel core.<ref name="Steuber"/><ref name="review"/> This site consists of residues that are most likely involved in the catalytic reaction (including residues Tyr48, Lys77, His110).<ref name="Steuber"/> 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="review"/> Trp111 and the nicotinamide moiety of NADPH 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"/> | 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="Steuber"/><ref name="review"/> 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 deeply buried inside the barrel core.<ref name="Steuber"/><ref name="review"/> This site consists of residues that are most likely involved in the catalytic reaction (including residues Tyr48, Lys77, His110).<ref name="Steuber"/> 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="review"/> Trp111 and the nicotinamide moiety of NADPH interact with the head group of most <scene name='Sandbox_Reserved_339/Ligand/1'>ligands</scene>.<ref name="Steuber"/> Hydrophobic contacts can be formed by the side-chains of Trp20, Val47, Trp79, and Trp219.<ref name="Steuber"/> | ||
===Aldose Reductase Structure and Inhibitors=== | ===Aldose Reductase Structure and Inhibitors=== | ||
Most inhibitors that bind tightly to aldose reductase have a polar group, which is usually a carboxylate, that is attached to a hydrophobic core.<ref name="review"/> Inhibitors bind with their polar head group oriented close to the pyridine ring and usually form hydrogen bonds with Tyr48, His110, and Tyr111.<ref name="review"/> Hydrophobic interactions between the inhibitor and the residues that line the active site help to stabilize the ternary enzyme-coenzyme-inhibitor complex. <ref name="review"/> | Most inhibitors that bind tightly to aldose reductase have a polar group, which is usually a carboxylate, that is attached to a hydrophobic core.<ref name="review"/> Inhibitors bind with their polar head group oriented close to the pyridine ring and usually form hydrogen bonds with Tyr48, His110, and Tyr111.<ref name="review"/> Hydrophobic interactions between the inhibitor and the residues that line the active site help to stabilize the ternary enzyme-coenzyme-inhibitor complex. <ref name="review"/> | ||