Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.1.1.21 (aldose reductase)
3,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Direct investigation of the polyol pathway is rarely possible in studies of human diabetes. A spectrophotometric assay has been developed for the measurement of aldose reductase and sorbitol dehydrogenase activity in the neutrophil. Neutrophil aldose reductase activity was increased in patients with Type 1 diabetes with complications (median 40 (interquartile range 28-48) u, where 1 unit of enzyme activity = nmol NADPH min-1 10(8)-cells-1) compared with those without complications (20 (16-36) u, p less than 0.01) and normal control subjects (20 (8-36) u, p less than 0.01). In Type 2 diabetes, patients with complications also had higher aldose reductase activity (40 (28-52) u) than those without complications (24 (16-36) u, p less than 0.01). There were no differences between patients without complications and normal control subjects. Sorbitol dehydrogenase activity was decreased in diabetic patients (p less than 0.02) but not significantly different between diabetic patients with and without complications.
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PMID:Neutrophil aldose reductase activity and its association with established diabetic microvascular complications. 183 May 28

Osmoregulation in inner medullary cells depends in part on cellular accumulation of sorbitol, the production of which from glucose is catalyzed by aldose reductase. To identify nephron segments that contain aldose reductase, we developed a fluorometric ultramicroassay to measure aldose reductase activity in microdissected nephron segments from collagenase-treated kidneys of Sprague-Dawley rats. DL-Glyceraldehyde (10 mM) was used as a substrate. Substantial aldose reductase activities were found in all three inner medullary renal tubule segments: thin descending limbs, thin ascending limbs, and inner medullary collecting ducts. Activity increased with depth into the inner medulla in all three segments. When aldose reductase activities were normalized by cell volume the activities in the three inner medullary segments were similar. Little or no aldose reductase activity was measured in glomeruli or any cortical or outer medullary nephron segment. Both proximal convoluted and proximal straight tubules were found to have a substantial capacity to reduce DL-glyceraldehyde, but the finding of greater reductase activity with D-glucuronate (10 mM) than with D-xylose (10 mM) indicated that the activity was due to aldehyde reductase. Sorbitol dehydrogenase (measured by a similar ultramicroassay method) was present in substantial amounts in proximal tubules, but not in inner medullary collecting ducts. The overall pattern of enzyme activities is consistent with the proposed osmoregulatory role for sorbitol in all three inner medullary renal tubule segments.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Aldose reductase activities in microdissected rat renal tubule segments. 249 37

A double mutant strain (UR3) of Rhizobium meliloti L5-30 was isolated from a phosphoglucose isomerase mutant (UR1) on the basis of its resistance to fructose inhibition when grown on fructose-rich medium. UR3 lacked both phosphoglucose isomerase and fructokinase activity. A mutant strain (UR4) lacking only the fructokinase activity was derived from UR3; it grew on the same carbon sources as the parent strain, but not on fructose, mannitol, or sorbitol. A spontaneous revertant (UR5) of normal growth phenotype contained fructokinase activity. A fructose transport system was found in L5-30, UR4, and UR5 grown in arabinose-fructose minimal medium. No fructose uptake activity was detected when L5-30 and UR5 were grown on arabinose minimal medium, but this activity was present in strain UR4. Free fructose was concentrated intracellularly by UR4 > 200-fold above the external level. A partial transformation of fructose into mannitol and sorbitol was detected by enzymatic analysis of the uptake products. Polyol dehydrogenase activity was detected in UR4 grown in arabinose-fructose minimal medium. The induction pattern of polyol dehydrogenase activities in this strain might be due to slight intracellular fructose accumulation.
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PMID:Biochemical characterization of a fructokinase mutant of Rhizobium meliloti. 625 86

Intraneuronal accumulations of sorbitol and fructose have been postulated to predispose the nervous system to the cerebral edema associated with the treatment of diabetic ketoacidosis. In the present study, the enzymes of the pathway for the production of sorbitol and fructose, aldose reductase and sorbitol dehydrogenase, were localized histochemically in brain, spinal cord and sciatic nerve. Enzyme activity was limited to the choroidal epithelium, ependymal cells, and pia mater in normal, 2- and 10-week streptozotocin diabetic and vehicle-treated rats. Sorbitol dehydrogenase activity was located in blood vessels and perineurium of the sciatic nerve in these groups of rats. Comparison of diabetic and vehicle groups did not demonstrate any alteration in the activity of either enzyme in the central nervous system. However, there was a decrease in sorbitol dehydrogenase activity in the blood vessels in the sciatic nerve in 50% of the 10-week diabetic rats.
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PMID:Localization of aldose reductase and sorbitol dehydrogenase in the nervous system of normal and diabetic rats. 680 Jan 75

Sorbitol dehydrogenase (Sord) catalyzes the interconversion of sorbitol and fructose and is functionally important both in the metabolism of dietary sorbitol and as a source of fructose in semen. Together with aldose reductase, Sord forms the polyol pathway, which plays an important role in the etiology of diabetic complications. The Sord-deficient mouse (C57BL/ LiA) is very useful in animal model studies of the involvement of the polyol pathway in both diabetic and congenital cataracts. To understand more about this strain, we characterized the molecular basis underlying this Sord deficiency and found that this was due to a point mutation in the exon 8/intron 8 junction. Substitution of an A for G at the first position of the strictly conserved GT donor completely abolished normal splicing of exon 8. Aberrant splicing of this junction generates at least three types of transcripts: one lacking exon 8, another that has a truncated exon 8, and a third that contains intron sequences. We have devised two convenient PCR-based methods to identify this mutation in C57BL/LiA mice. These methods are useful in animal experiments that involve cross-breeding with these mice because they allow early determination of genotype without the need to sacrifice the animals for enzyme assay.
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PMID:Aberrant mRNA splicing causes sorbitol dehydrogenase deficiency in C57BL/LiA mice. 940 62

There is strong evidence to show that diabetes is associated with increased oxidative stress. However, the source of this oxidative stress remains unclear. Using transgenic mice that overexpress aldose reductase (AR) in their lenses, we found that the flux of glucose through the polyol pathway is the major cause of hyperglycemic oxidative stress in this tissue. The substantial decrease in the level of reduced glutathione (GSH) with concomitant rise in the level of lipid peroxidation product malondialdehyde (MDA) in the lens of transgenic mice, but not in the nontransgenic mice, suggests that glucose autoxidation and nonenzymatic glycation do not contribute significantly to oxidative stress in diabetic lenses. AR reduction of glucose to sorbitol probably contributes to oxidative stress by depleting its cofactor NADPH, which is also required for the regeneration of GSH. Sorbitol dehydrogenase, the second enzyme in the polyol pathway that converts sorbitol to fructose, also contributes to oxidative stress, most likely because depletion of its cofactor NAD+ leads to more glucose being channeled through the polyol pathway. Despite a more than 100% increase of MDA, oxidative stress plays only a minor role in the development of cataract in this acute diabetic cataract model. However, chronic oxidative stress generated by the polyol pathway is likely to be an important contributing factor in the slow-developing diabetic cataract as well as in the development of other diabetic complications.--Lee, A. Y. W., Chung, S. S. M. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J. 13, 23-30 (1999)
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PMID:Contributions of polyol pathway to oxidative stress in diabetic cataract. 987 26

Sorbitol dehydrogenase (hSDH) and aldose reductase form the polyol pathway that interconverts glucose and fructose. Redox changes from overproduction of the coenzyme NADH by SDH may play a role in diabetes-induced dysfunction in sensitive tissues, making SDH a therapeutic target for diabetic complications. We have purified and determined the crystal structures of human SDH alone, SDH with NAD(+), and SDH with NADH and an inhibitor that is competitive with fructose. hSDH is a tetramer of identical, catalytically active subunits. In the apo and NAD(+) complex, the catalytic zinc is coordinated by His69, Cys44, Glu70, and a water molecule. The inhibitor coordinates the zinc through an oxygen and a nitrogen atom with the concomitant dissociation of Glu70. The inhibitor forms hydrophobic interactions to NADH and likely sterically occludes substrate binding. The structure of the inhibitor complex provides a framework for developing more potent inhibitors of hSDH.
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PMID:X-ray crystallographic and kinetic studies of human sorbitol dehydrogenase. 1296 26

Sorbitol dehydrogenase (SDH) is a polyol pathway enzyme that catalyzes conversion of sorbitol to fructose. Recent studies have demonstrated that activation of aldose reductase, the first enzyme of the polyol pathway, is a key response to ischemia and that inhibition of aldose reductase reduces myocardial ischemic injury. In our efforts to understand the role of pathway in affecting metabolism under normoxic and ischemic conditions, as well as in ischemic injury in myocardium, we investigated the importance of SDH by use of a specific inhibitor (SDI), CP-470,711. SDH inhibition increased glucose oxidation, whereas palmitate oxidation remained unaffected. Global ischemia increased myocardial SDH activity by approximately 1.5 fold. The tissue lactate/pyruvate ratio, a measure of cytosolic NADH/NAD+, was reduced by SDH inhibition under both normoxic and ischemic conditions. ATP was higher in SDI hearts during ischemia and reperfusion. Creatine kinase release during reperfusion, a marker of myocardial ischemic injury, was markedly attenuated in SDH-inhibited hearts. These data indicate that myocardial SDH activation is a component of ischemic response and that interventions that inhibit SDH protect ischemic myocardium. Furthermore, these data identify SDH as a novel target for adjunctive cardioprotective interventions.
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PMID:Sorbitol dehydrogenase: a novel target for adjunctive protection of ischemic myocardium. 1452 43

During the epididymal transit, male gametes acquire new surface proteins necessary for their fertilizing ability. We have previously shown that membranous vesicles, called epididymosomes, interact with sperm surface within the epididymal fluid allowing transfer of some proteins to different subcellular compartments of spermatozoa. We previously showed that one of the major proteins associated with epididymosomes was an aldose reductase (gene: AKR1B5) and confirmed that aldose reductase is located in the epithelial cells bordering the intraluminal compartment of the epididymis. The present study shows that cytosolic aldose reductase activity was maximal in the proximal and middle segments of the epididymis and decreased in the distal epididymis. Western and Northern blot analysis confirmed the distribution pattern of aldose reductase and of the encoding mRNA. The optimal pH of epididymal aldose reductase was 6.0-6.5 when glucose was used as a substrate; this corresponds to the pH of the intraluminal epididymal fluid. In order to evaluate the possible involvement of sorbitol in sperm physiology, Western blot of tissue homogenates were probed with an anti-sorbitol dehydrogenase antibody. The amount of enzyme immunodetected was higher in the proximal and distal segments of the epididymis when compared to the amount detectable in the middle segment of the epididymis. Sorbitol dehydrogenase activity as well as the level of the encoding mRNA showed the same pattern of distribution. Furthermore, immunohistological studies using the anti-sorbitol dehydrogenase revealed that this enzyme was synthesized by the epididymal epithelial cells bordering the intraluminal compartment. Knowing the importance of sorbitol and fructose in sperm metabolism, we hypothesized that the polyol pathway is involved in the modulation of sperm motility within the epididymis.
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PMID:Polyol pathway along the bovine epididymis. 1545 14

This study evaluated the effects of retinal ischemia-reperfusion (IR) injury and pre-treatment with the potent and specific aldose reductase inhibitor fidarestat on apoptosis, aldose reductase and sorbitol dehydrogenase expression, sorbitol pathway intermediate concentrations, and oxidative-nitrosative stress. Female Wistar rats were pre-treated with either vehicle (N-methyl-D-glucamine) or fidarestat, 32 mg kg(-1) d(-1) for both, in the right jugular vein, for 3 consecutive days. A group of vehicle- and fidarestat-treated rats were subjected to 45-min retinal ischemia followed by 24-h reperfusion. Ischemia was induced 30 min after the last vehicle or fidarestat administration. Retinal IR resulted in a remarkable increase in retinal cell death. The number of TUNEL-positive nuclei increased 48-fold in the IR group compared with non-ischemic controls (p<0.01), and this increase was partially prevented by fidarestat. AR expression (Western blot analysis) increased by 19% in the IR group (p<0.05), and this increase was prevented by fidarestat. Sorbitol dehydrogenase and nitrated protein expressions were similar among all experimental groups. Retinal sorbitol concentrations tended to increase in the IR group but the difference with non-ischemic controls did not achieve statistical significance (p=0.08). Retinal fructose concentrations were 2.2-fold greater in the IR group than in the non-ischemic controls (p<0.05). Fidarestat pre-treatment of rats subjected to IR reduced retinal sorbitol concentration to the levels in non-ischemic controls. Retinal fructose concentrations were reduced by 41% in fidarestat-pre-treated IR group vs. untreated ischemic controls (p=0.0517), but remained 30% higher than in the non-ischemic control group. In conclusion, IR injury to rat retina is associated with a dramatic increase in cell death, elevated AR expression and sorbitol pathway intermediate accumulation. These changes were prevented or alleviated by the AR inhibitor fidarestat. The results identify AR as an important therapeutic target for diseases involving IR injury, and provide the rationale for development of fidarestat and other AR inhibitors.
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PMID:Evaluation of the aldose reductase inhibitor fidarestat on ischemia-reperfusion injury in rat retina. 2051 33


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