Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.6.1.3 (ATPase)
 65,361 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phenylketonuric squirrels have shown marked inhibition of alkaline phosphatase in the olfactory lobes and cerebral hemispheres, whereas the Na+-K+-ATPase remained less altered. In the pathogenesis of phenylketonuria inhibition of alkaline phosphatase at the level of "Blood-Brain Barrier" (BBB), leads transport system to impaired functioning.
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PMID:Imbalance in the activities of alkaline phosphatase and Na+-K+-ATPase in the brain of experimentally induced phenylketonuric squirrels (Funambulus palmarum). 21 45

The effects of phenylalanine (PHE) and its deaminated metabolites phenylpyruvate (PHP), phenyllactate (PHL) and phenylacetate (PHA) on sodium and potassium activated adenosinetriphosphatase (Na+,K+-ATPase) in synaptosomes from rat brain were investigated. At very low concentrations (5-10 microM). PHE, PHL and PHA inhibited the activity, while PHP stimulated the activity. At intermediate concentrations (50-100 microM), all compounds had no effect, but at higher (0.5-1.0 mM) concentrations they inhibited the enzyme activity. Thus all the compounds tested showed a biphasic effect on the enzyme activity. Hydroxylamine inhibited the Na+,K+-ATPase activity when present alone; simultaneous addition of hydroxylamine and PHE, however, eliminated the inhibitory effects of each other. Reversal of mutual inhibition also occurred in the presence of hydroxylamine and very low (5-10 microM) concentrations of PHL or PHA. The inhibitory effects of PHE at aLl concentrations, and of PHL or PHA at low concentrations, were also eliminated in the presence of EGTA. The data indicate that inhibition of brain membrane Na+,K+-ATPase by PHE and by low concentrations of PHL and PHA may involve metal ions, but that the inhibition by high concentrations of these metabolites must occur by a different mechanism. Since Na+,K+-ATPase plays a central role in neuronal function, and the presence of excess PHE and its deaminated metabolites occurs in brain tissue under conditions of experimentally induced hyperphenylalaninemia and genetic phenylketonuria, the neurologic impairment in experimental and genetic PKU may in part be related to the deleterious effects of these compounds on brain ATPase.
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PMID:Effects of phenylalanine and its deaminated metabolites on Na+,K+-ATPase activity in synaptosomes from rat brain. 628 50

Our objective was to investigate the effect of alanine administration on Na+,K+-ATPase activity in cerebral cortex of rats subjected to chemically-induced phenylketonuria. Wistar rats were treated from the 6th to the 28th day of life with subcutaneous injections of either 2.6 micromol alanine or 5.2 micromol phenylalanine plus 2.6 micromol alpha-methylphenylalanine per g body weight or phenylalanine plus alpha-methylphenylalanine plus alanine in the same doses or equivalent volumes of 0.15 M saline. The animals were killed on the 29th or 60th day of life. Synaptic plasma membrane from cerebral cortex was prepared for Na+,K+-ATPase activity determination. The results showed that alanine injection prevents the decrease of Na+,K+-ATPase activity in animals subjected to experimental phenylketonuria. Therefore, in case the same effects are achieved with ingested alanine, it is possible that alanine supplementation may be an important dietary adjuvant for phenylketonuric patients.
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PMID:Alanine prevents the decrease of Na+,K+-ATPase activity in experimental phenylketonuria. 1048 11

Na+, K+-ATPase activity was measured in synaptic plasma membrane from cerebral cortex of Wistar rats subjected to experimental phenylketonuria, i.e., chemical hyperphenylalaninemia induced by subcutaneous administration of 5.2 micromol phenylalanine / g body weight (twice a day) plus 0.9 micromol p-chlorophenylalanine / g body weight (once a day). The treatment was performed from the 6th to the 14th postpartum day and rats were killed 12 h after the last injection. Synaptic plasma membrane from cerebral cortex was prepared by a discontinuous density sucrose gradient for Na+, K+-ATPase activity determination. The results showed that the enzyme activity was decreased by 30% in animals subjected to experimental phenylketonuria when compared to control. The in vitro effects of the drugs on Na+, K+-ATPase activity were also investigated. Phenylalanine and p-chlorophenylalanine inhibited the enzyme activity and this inhibition was reversed by alanine. In addition, competition between phenylalanine and p-chlorophenylalanine for binding to the enzyme was observed, suggesting a common binding site for these substances. Our results suggest that reduction of Na+, K+-ATPase activity may be one of the mechanisms related to the brain dysfunction observed in human PKU.
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PMID:Effect of phenylalanine and p-chlorophenylalanine on Na+, K+-ATPase activity in the synaptic plasma membrane from the cerebral cortex of rats. 1109 77

The in vitro effects of phenylalanine or alanine alone or combined on Na+, K+-ATPase activity in membranes from human platelets were investigated. The enzyme activity was assayed in membranes prepared from platelet-rich plasma of healthy donors. Phenylalanine or alanine were added to the assay to final concentrations of 0.3 to 1.2 mM, similar to those found in plasma of phenylketonuric patients. Phenylalanine inhibited Na+, K+-ATPase activity by 20-50% [F(4,25)=11.47 ; p<0.001]. Alanine had no effect on Na+, K+-ATPase activity but when combined with phenylalanine prevented the enzyme inhibition. These results, allied to others previously reported on brain Na+, K+-ATPase activity, may reflect a general inhibitory effect of phenylalanine on this important enzyme activity. Therefore, it is possible that measurement of Na+, K+-ATPase activity in platelets from PKU patients may be a useful peripheral marker for the neurotoxic effects of phenylalanine.
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PMID:Platelet Na+, K+-ATPase activity as a possible peripheral marker for the neurotoxic effects of phenylalanine in phenylketonuria. 1109 78

The effect of different L-phenylalanine (Phe) concentrations (0.12-1.8 mM) on acetylcholinesterase (AChE), (Na(+), K(+))-ATPase and Mg(2+)-ATPase activities was investigated in homogenates of adult and aged rat whole brain at 37 degrees C. Adult and aged rat experiments were necessary in relation to phenylketonuria (PKU) since phenylketonuric patients usually discontinue their therapeutic special diet when they reach adulthood. Diet discontinuation results in the pathological increase of Phe concentration in plasma and consequently in brain. AChE activity in adult brain homogenates showed a decrease up to 18% (P<0.01) with 0.48--1.8 mM Phe preincubated for 1 h. Adult brain Na(+), K(+)-ATPase was stimulated by 30--35% (P<0.01) in the presence of 0.48--1.8 mM Phe. However, high Phe concentrations were not able to affect the activities of AChE and Na(+), K(+)-ATPase, when preincubated with aged brain homogenate for 3 h. Moreover, high Phe concentrations appeared unable to affect the activity of eel E. electricus pure AChE inhibited about 30% (P<0.001) by the free radical system H(2)O(2)/Fe(2+). Also, the antagonists of alpha- and beta-adrenergic receptors (phenoxybenzamine and propranolol, respectively) inhibited adult rat brain Na(+), K(+)-ATPase activity about 30--40% (P<0.01) and Phe was unable to change this action. It is suggested that: (a) The inhibitory effect of Phe on brain AChE and its stimulatory effect on brain Na(+), K(+)-ATPase are decreased with age; (b) These effects may be influenced by aging factors, such as free radical action and/or reduced density of alpha- and beta-adrenergic receptors in the tissue.
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PMID:Effects of L-phenylalanine on acetylcholinesterase and Na(+), K(+)-ATPase activities in adult and aged rat brain. 1129 14

Na(+), K(+)-ATPase activity was determined in erythrocyte membranes from 12 phenylketonuric patients of both sexes, aged 8.8 +/- 5.0 y, with plasma phenylalanine levels of 0.64 +/- 0.31 mM. The in vitro effects of phenylalanine and alanine on the enzyme activity in erythrocyte membranes from healthy individuals were also investigated. We observed that Na(+), K(+)-ATPase activity was decreased by 31% in erythrocytes from phenylketonuric patients compared with normal age-matched individuals (p < 0.01). We also observed a significant negative correlation between erythrocyte Na(+), K(+)-ATPase activity and plasma phenylalanine levels (r = -0.65; p < 0.05). All PKU patients with plasma phenylalanine levels higher than 0.3 mM had erythrocyte Na(+), K(+)-ATPase activity below the normal range. Phenylalanine inhibited in vitro erythrocyte Na(+), K(+)-ATPase activity by 22 to 34%, whereas alanine had no effect on this activity. However, when combined with phenylalanine, alanine prevented Na(+) K(+)-ATPase inhibition. Considering that reduction of Na(+), K(+)-ATPase activity occurs in various neurodegenerative disorders leading to neuronal loss, our previous observations showing a significant reduction of Na(+), K(+)-ATPase activity in brain cortex of rats subjected to experimental phenylketonuria and the present results, it is proposed that determination of Na(+), K(+)-ATPase activity in erythrocytes may be a useful peripheral marker for the neurotoxic effect of phenylalanine in phenylketonuria.
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PMID:Reduced Na(+), K(+)-ATPase activity in erythrocyte membranes from patients with phenylketonuria. 1142 Apr 19

The effect of different L-phenylalanine (Phe) concentrations (0.12-12.1 mM) on acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+-ATPase activities was evaluated in homogenates of suckling rat frontal cortex, hippocampus and hypothalamus. Phe, at high concentrations, reduced AChE activity in frontal cortex and hippocampus by 18%-20%. On the contrary, the enzyme activity was unaltered in the hypothalamus. Na+,K+-ATPase was stimulated by high levels of the amino acid, both in the frontal cortex and the hypothalamus by 60%, whereas it was inhibited in the hippocampus by 40%. Mg2+-ATPase was not influenced by Phe. It is suggested that: a) In the frontal cortex, the improper acetylcholine (ACh) release, due to AChE inhibition by Phe, combined with the stimulation of Na+,K+-ATPase, possibly explain tremor and the hyperkinetic behaviour in patients with classical phenylketonuria (PKU). b) In the hippocampus, inhibition of AChE by Phe could lead to problems in memory, while Na+,K+-ATPase inhibition by Phe may induce metabolic disorders and electrical instability of the synaptosomal membrane. c) In the hypothalamus, the behavioral problems in PKU "off diet" may be related to noradrenaline (NA) levels, which are probably correlated with the modulated Na+,K+-ATPase by Phe.
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PMID:Effects of L-phenylalanine on acetylcholinesterase and Na+,K+-ATPase activities in suckling rat frontal cortex, hippocampus and hypothalamus. 1192 33

Classical phenylketonuria (PKU) is caused by deficiency of phenylalanine hydroxylase, resulting in an accumulation of its upstream metabolite phenylalanine in brain tissue and cerebrospinal fluid of PKU patients. PKU is neuropathologically characterized by reduced dendritic arborization, loss of synapses, and neurodegeneration. We investigated whether increased concentrations of phenylalanine cause reduced synaptic density and alter dendritic branching. We treated primary cortical neurons differentiated for 21 d in vitro with 5 mM phenylalanine in the presence of all essential amino acids. Immunocytochemical analysis of 12 and 21 d in vitro primary neurons revealed no changes of dendritic morphology or neuronal viability but a significant difference in synaptic density, suggesting that elevated concentrations of extracellular phenylalanine cause an impairment of synaptogenesis. Although impairment of cerebral energy metabolism has been identified as an important pathophysiological principal in many diseases, respiratory chain function has not been extensively studied in PKU before. We investigated whether phenylalanine inhibits respiratory chain complexes I-V. In vitro analysis revealed no inhibitory effect of phenylalanine on complexes I-V, but an inhibition of pyruvate kinase, a key enzyme of glycolysis, catalyzing the formation of pyruvate. Pyruvate kinase is part of the enzyme assay to investigate enzyme activity of mitochondrial complex V and it remains to be elucidated whether this finding is relevant in vivo. In conclusion, elevated concentrations of phenylalanine might be involved in mechanisms underlying impaired synaptogenesis in PKU, supporting the common therapeutic strategy to reduce phenylalanine concentrations in the brain to prevent neurodegeneration.
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PMID:Phenylalanine reduces synaptic density in mixed cortical cultures from mice. 1654 26

Classic phenylketonuria (PKU) is characterized by brain lesions. However, its underlying neurotoxic mechanisms remain unknown. Based on our previous studies, we hypothesized that calcium might participate in PKU-associated neuropathy. In cultured cortical neurons, cytoplasmic free calcium concentration ([Ca(2+)](i)) decreased dramatically when treatment with phenylalanine (Phe) and phenyllactic acid, while phenylacetic acid treatment immediately increased [Ca(2+)](i), which began to decrease after 3 min. Moreover, [Ca(2+)](i) decreased dramatically after Phe treatment in the presence of EGTA suggesting that Phe might increase [Ca(2+)](i) efflux. Phe-induced [Ca(2+)](i) decrease was strongly inhibited by vanadate, a non-specific plasma membrane Ca(2+)-ATPase (PMCA) antagonist, suggesting that Phe might increase [Ca(2+)](i) efflux throught modulating PMCA. These findings were further supported by the facts that Phe could increase membrance (45)Ca-uptake capability and PMCA activity. In contrast, treatment of KBR7943 or thapsigargin, antagonists to Na/Ca Exchanger (NCX) and Sarco/Endoplasmic reticulum Ca(2+)-ATPase (SERCA), respectively, did not elicit any changes in [Ca(2+)](i). Specific siRNA against PMCA had an effect similar to vanadate. Since the brain injury induced by phenylalaninemia was thought to be a chronic process, we cultured cortical neurons in the presence of Phe for 2 weeks and measured [Ca(2+)](i), PMCA activity and (45)Ca-uptake capability at days 3, 7, 9 and 14, respectively. PMCA activity and (45)Ca-uptake capability decreased from day 9, at the same time [Ca(2+)](i) increase was observed. In conclusion, PMCA participate in regulating Phe-induced initial rapid decrease in [Ca(2+)](i) and subsequent long-term increase in [Ca(2+)](i).
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PMID:Effects of phenylalanine and its metabolites on cytoplasmic free calcium in cortical neurons. 1740 56


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