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 <scene name='Sandbox_Reserved_339/Helices_and_strands/1'>13 β-strands and 10 α-helices</scene>. 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 <scene name='Sandbox_Reserved_339/Nadph/2'>NADPH</scene> 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 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 <scene name='Sandbox_Reserved_339/Helices_and_strands/1'>13 β-strands and 10 α-helices</scene>. 13 β-strands and 10 α-helices 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 <scene name='Sandbox_Reserved_339/Nadph/2'>NADPH</scene> 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"/> | ||