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:1.2.1.13 (glyceraldehyde-3-phosphate dehydrogenase)
6,511 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies on the toxicokinetics and biochemical effects of acrylamide are reviewed in regard to their implications concerning the mechanism of acrylamide induced neuropathy. Specifically, investigations of the effects of acrylamide on several glycolytic enzymes including neuron-specific enolase and glyceraldehyde-3-phosphate dehydrogenase are evaluated. Both of these enzymes are decreased in activity in animals exhibiting clinical signs of neuropathy induced by acrylamide. The significance of these findings in terms of the mechanism of action of acrylamide is discussed.
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PMID:Biochemical studies of acrylamide neuropathy. 293 50

Energy metabolism was examined in rat sciatic nerve before and after induction of neuropathy by treatment with acrylamide monomer. The in vivo activities of two glycolytic enzymes, glyceraldehyde-3-phosphate dehydrogenase and nerve-specific enolase, were resistant to acrylamide. The levels of adenosine 5'-triphosphate and creatine phosphate were also unaffected by acrylamide after either short-term or long-term treatment. The turnover of high-energy phosphate was somewhat reduced in the nerves of severely intoxicated animals. These findings cast doubt on the hypothesis that acrylamide neuropathy begins with an attack on the means of generating metabolic energy, although the eventual failure of one or more energy-consuming processes in peripheral nerve remains likely.
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PMID:Acrylamide neuropathy in the rat: effects on energy metabolism in sciatic nerve. 298 75

The effect of acrylamide and six analogues on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and enolase in sciatic nerve was examined in rats after their prolonged administration in drinking water. After 15 days' treatment with acrylamide and N-isopropylacrylamide, slight signs of peripheral neuropathy were produced with no changes in the activity of either enzyme. N,N-dimethylacrylamide, a non-neurotoxic analogue, produced only body weight loss at this stage. After 30 days' treatment, acrylamide and N-isopropylacrylamide produced moderate signs of neuropathy, but no changes in enzyme activity. N,N-dimethylacrylamide produced a reduction in GAPDH activity as well as body weight loss. After 45 days' treatment, acrylamide, N-isopropylacrylamide, N-hydroxymethylacrylamide and N-methylacrylamide produced severe signs of neuropathy as well as body weight loss. All these analogues also produced a reduction in the two enzyme activities, except for enolase after N-isopropylacrylamide. N,N-dimethylacrylamide produced inhibition of GAPDH as well as body weight loss without neuropathy. N-tert-butylacrylamide and N,N'-methylene-bis-acrylamide induced neither neuropathy nor inhibition of either enzyme.
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PMID:Effect of acrylamide and related compounds on glycolytic enzymes in rat sciatic nerve in vivo. 300 83

The in vitro effect of acrylamide and its analogues on rat brain glycolytic enzymes was examined to elucidate the biochemical lesions responsible for the pathogenesis of acrylamide-induced neuropathy. All test compounds inhibited glyceraldehyde-3-phosphate dehydrogenase, irrespective of their neurotoxicity, and their inhibitory potency was a linear function of the rate constant with reduced glutathione. Phosphofructokinase was also inhibited by some of the test compounds, independently of their neurotoxicity. The rate-limiting enzymes in glycolysis, hexokinase and pyruvate kinase, were not inhibited by acrylamide.
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PMID:Effect of acrylamide and related compounds on glycolytic enzymes of rat brain. 316 Dec 19

In previous investigations acrylamide was found to inhibit several enzymes of glycolysis both in vitro and in vivo. The present study examines the characteristics of the in vitro inhibition of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and compares the in vivo effects of acrylamide on GAPDH activity to other analogs. Inhibition of GAPDH produced by acrylamide was characteristic of an irreversible or slowly reversible mechanism. In vivo, GAPDH activity was determined in sciatic nerve, brain, skeletal muscle and liver after cumulative doses of 250, 350 or 500 mg/kg of acrylamide. Specific activities were significantly lower in extensor muscle and liver after the 250 mg/kg dose. Activities in brain and sciatic nerve tended to be decreased but the differences were not statistically significant. Specific activity of GAPDH was decreased in medulla pons, cerebellum and the rest of the brain after a 350 mg/kg cumulative dose of acrylamide, although protein concentrations were not different from those in controls. The maximum decrease was about 20%. Treatment with acrylamide, methylene-bis-acrylamide (non-neurotoxic), or N-isopropylacrylamide (neurotoxic) significantly decreased the weight of the cortex and associated brain areas as well as general body weights. No signs of developing neuropathy were observed during treatment with methylene-bis-acrylamide to a cumulative dose (8.1 mmoles/kg) equivalent to that of acrylamide causing frank paralysis. Although the compound exhibited some ability to inhibit GAPDH in vitro, no decrease in GAPDH activity was found in rat brain. Treatment with N-isopropylacrylamide resulted in progressive neurologic impairment. After treatment to a cumulative dose of the compound causing a severe hind-limb paralysis (9.2 mmoles/kg), a small but significant decrease in GAPDH was found in the three areas of brain examined.
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PMID:Inhibition of glyceraldehyde-3-phosphate dehydrogenase in tissues of the rat by acrylamide and related compounds. 404 9

The contribution of defective energy metabolism to the induction of neuronal pathology by p-bromophenylacetylurea (BPAU) was examined in several ways. It was found that a saturated aqueous solution of BPAU had no effect on the activity of crystalline glyceraldehyde-3-phosphate dehydrogenase (GAPDH) or phosphofructokinase (PFK). In rats with total hindlimb paralysis from treatment with BPAU (400 mg/kg), the endogenous GAPDH and PFK of sciatic nerve showed normal activity. Endogenous enolase and nerve-specific enolase activities were likewise unaffected. Consequently, it appeared improbable that BPAU neuropathy involves impaired glycolysis. This conclusion was supported by the failure to prevent hindlimb weakness by feeding pyruvate, a substrate for the Krebs cycle. To test for interference with glycolysis at other steps, or for an impairment in oxidative phosphorylation, adenosine triphosphate (ATP) and creatine phosphate were measured. The amounts of high energy phosphates in nerves of paralyzed animals were found to be the same as in nerves of untreated and vehicle-treated controls. A similar observation was made in nerves regenerating from a crush injury. To test turnover, ATP and creatine phosphate were measured in nerves exposed to an N2 atmosphere in vitro. Since the high energy phosphates disappeared at the same rates in all groups, it was concluded that BPAU neuropathy does not alter energy utilization. In our view, BPAU neuropathy arises by a mechanism that does not depend on altered energy metabolism.
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PMID:Unimpaired energy metabolism in experimental neuropathy induced by p-bromophenylacetylurea. 610 Apr 57

Inhibition of the sulfhydryl enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) by 2,5-hexanedione (2,5-HD) was found to be irreversible, proceeding via a reversible enzyme-inhibitor intermediate, while acetone was a weak reversible inhibitor. Comparison of 2,5-HD and acetone with p-chloromercuribenzoate (PCMB) and N-ethylmaleimide (NEM) demonstrated that the former are not significant sulfhydryl reagents, since they must be present at more than 10(4) times higher concentrations than PCMB or NEM to effect measurable inhibition of this enzyme. Thus it is unlikely that inhibition of GAPDH by 2,5-HD has any significance in the molecular pathogenesis of hexane neuropathy. The irreversibility of 2,5-HD inhibition, on the othe hand, suggests that 2,5-HD reacts with amino groups rather than sulfhydryl groups on proteins. This reaction is proposed as the molecular lesion in hexane neuropathy.
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PMID:Studies of the molecular pathogenesis of hexane neuropathy. I. evaluation of the inhibition of glyceraldehyde-3-phosphate dehydrogenase by 2,5-hexanedione. 742 Apr 69

The sequelae of chronic hyperglycemia in diabetes of all phenotypes are divided into microvascular and macrovascular complications. Microvascular disease causes blindness, renal failure, and neuropathy, and diabetes-accelerated macrovascular disease causes excessive risk for myocardial infarction, stroke, and lower limb amputation. The link between chronic hyperglycemia and vascular damage has been established by four independent biochemical abnormalities: increased polyol pathway flux, increased formation of advanced glycation end-products (AGEs), activation of protein kinase C (PKC), and increased hexosamine pathway flux. These seemingly unrelated pathways have an underlying common denominator: overproduction of superoxide by the mitochondrial electron transport chain. Mitochondrial reactive oxygen species (ROS) partially inhibit the glycolytic enzymes glyceraldehyde-3-phosphate dehydrogenase, which diverts increased substrate flux from glycolysis to pathways of glucose overutilization. Preliminary experimental evidence in vivo suggests that this new paradigm provides a novel basis for research and drug development.
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PMID:Pathophysiological mechanisms of diabetic angiopathy. 1262 64

Recent work has demonstrated that hyperglycemia-induced overproduction of superoxide by the mitochondrial electron-transport chain triggers several pathways of injury [(protein kinase C (PKC), hexosamine and polyol pathway fluxes, advanced glycation end product formation (AGE)] involved in the pathogenesis of diabetic complications by inhibiting glyceraldehyde-3-phosphate dehydrogenase (GAPDH) activity. Increased oxidative and nitrosative stress activates the nuclear enzyme, poly(ADP-ribose) polymerase-1 (PARP). PARP activation, on one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport and ATP formation. On the other hand, PARP activation results in inhibition of GAPDH by poly-ADP-ribosylation. These processes result in acute endothelial dysfunction in diabetic blood vessels, which importantly contributes to the development of various diabetic complications. Accordingly, hyperglycemia-induced activation of PKC and AGE formation are prevented by inhibition of PARP activity. Furthermore, inhibition of PARP protects against diabetic cardiovascular dysfunction in rodent models of cardiomyopathy, nephropathy, neuropathy, and retinopathy. PARP activation is also present in microvasculature of human diabetic subjects. The present review focuses on the role of PARP in diabetic complications and emphasizes the therapeutic potential of PARP inhibition in the prevention or reversal of diabetic complications.
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PMID:The pathogenesis of diabetic complications: the role of DNA injury and poly(ADP-ribose) polymerase activation in peroxynitrite-mediated cytotoxicity. 1596 96

Type 2 diabetes mellitus caused by transfer of susceptible immortal gene from parent to progeny in individuals prone, and/or in contribution of factors such as obesity and physical inactivity results in chronic extracellular hyperglycemia due to insulin resistance or impaired glucose tolerance. Hyperglycemia leads to increased production of superoxide radical in mitochondrial electron transport chain, consequently, inhibit glyceraldehyde-3-phosphate dehydrogenase activity, increase the flux of substrates that direct the expression of genes responsible for activation of polyol, hexosamine, advanced glycation end products and protein kinase-C pathways enzymes. Simultaneously, these pathways add-up free radicals in the body, hamper cell redox state, alter genes of insulin sensitivity and are responsible for the diabetic complications like retinopathy, atherosclerosis, cardiovascular diseases, nephropathy and neuropathy. Experimental evidence suggests that the indoleamine hormone melatonin is capable of influencing in development of diabetic complications by neutralizing the unnecessary production of ROS, protection of beta cells, as they possess low antioxidant potential and normalize redox state in the cell. However, studies reported the beneficial effects of pharmacological supplementation of melatonin in humans but it has not been extensively studied in a multicountric, multicentric which should include all ethnic population.
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PMID:Type 2 diabetes mellitus: Role of melatonin and oxidative stress. 2545 Aug 12


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