Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mechanism for glycogen synthesis stimulation produced by adenosine, fructose, and glutamine has been investigated. We have analyzed the relationship between adenine nucleotides and glycogen metabolism rate-limiting enzymes upon hepatocyte incubation with these three compounds. In isolated hepatocytes, inhibition of AMP deaminase with erythro-9-(2-hydroxyl-3nonyl)adenine further increases the accumulation of AMP and the activation of glycogen synthase and phosphorylase by fructose. This ketose does not increase cyclic AMP or the activity of cyclic AMP-dependent protein kinase. Adenosine raises AMP and ATP concentration. This nucleotide also activates glycogen synthase and phosphorylase by covalent modification. The correlation coefficient between AMP and glycogen synthase activity is 0.974. Nitrobenzylthioinosine, a transport inhibitor of adenosine, blocks (by 50%) the effect of the nucleoside on AMP formation and glycogen synthase but not on phosphorylase. 2-Chloroadenosine and N6-phenylisopropyladenosine, nonmetabolizable analogues of adenosine, activate phosphorylase (6-fold) without increasing the concentration of adenine nucleotides or the activity of glycogen synthase. Cyclic AMP is not increased by adenosine in hepatocytes from starved rats but is in cells from fed animals. [Ethylenebis (oxyethylenenitrilo)]tetraacetic acid (EGTA) blocks by 60% the activation of phosphorylase by adenosine but not that of glycogen synthase. Glutamine also increases AMP concentration and glycogen synthase and phosphorylase activities, and these effects are blocked by 6-mercaptopurine, a purine synthesis inhibitor. Neither adenosine nor glutamine increases glucose 6-phosphate. It is proposed that the observed efficient glycogen synthesis from fructose, adenosine, and glutamine is due to the generation of AMP that activates glycogen synthase probably through increases in synthase phosphatase activity. It is also concluded that the activation of phosphorylase by the above-mentioned compounds can be triggered by metabolic changes.
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PMID:Role of AMP on the activation of glycogen synthase and phosphorylase by adenosine, fructose, and glutamine in rat hepatocytes. 210 32

Using AMP deaminase (AMP aminohydrolase; EC 3.5.4.6) purified from rabbit left-ventricular heart tissue, we report direct investigation of the potential for cardiac AMP deaminase activity to be regulated by kinase-mediated phosphorylation. Rabbit heart AMP deaminase served as a substrate for Ca2+/phospholipid-dependent protein kinase (protein kinase C; PKC) exclusively; no other mammalian protein kinase phosphorylated the enzyme. PKC-dependent AMP deaminase phosphorylation was rapid, linear with respect to time and the concentrations of PKC and AMP deaminase in the reaction, and inhibitable by staurosporine. Upon phosphorylation, the apparent Km of cardiac AMP deaminase decreased from 5.6 mM to 1.2 mM, without effect on the Vmax. Whether phosphorylated or not, rabbit heart AMP deaminase was inhibited by 1.0 mM GTP, which decreased the Vmax. by approximately 50% in each case. PKC-dependent phosphorylation of cardiac AMP deaminase did not alter the enzyme's allosterism toward millimolar ATP or ADP: both nucleotides at 1.0 mM concentration decreased the apparent Km to approximately 0.5 mM. Treatment of cardiac phospho-AMP deaminase with either the protein phosphatase calcineurin or alkaline phosphatase generated a dephosphorylated form which displayed molecular and kinetic properties identical with those of the originally isolated enzyme. These data raise the possibility that a phosphorylation-dephosphorylation mechanism may regulate flux through AMP deaminase in the heart under pathological conditions, such as myocardial ischaemia, characterized by PKC activation and adenylate depletion.
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PMID:Modulation of mammalian cardiac AMP deaminase by protein kinase C-mediated phosphorylation. 838 71

The properties of piglet cardiac AMP deaminase were determined and its regulation by pH, phosphate, nucleotides and phosphorylation is described. AMP deaminase purified from the ventricles of newborn piglet hearts displayed hyperbolic kinetics with a Km of 2 mM for 5'-AMP. The enzyme had a pH optimum of 7.0 and was strongly inhibited by inorganic phosphate. ATP decreased the Km of the native enzyme 3-fold, but did not significantly block the inhibitory effects of phosphate. Kinetic parameters were not significantly altered in the presence of adenosine, cyclic AMP and NAD+, whereas, the Km was decreased by 50% in the presence of NADH. Piglet cardiac AMP deaminase was phosphorylated by protein kinase C, resulting in a 2-fold increase in Vmax with no change in Km. However, incubation with cAMP-dependent protein kinase did not affect enzyme kinetics. The 80-85 kD protein subunit of piglet cardiac AMP deaminase immunoreacted with antisera raised against human erythrocyte AMP deaminase, rabbit heart AMP deaminase and human recombinant AMP deaminase 3 (isoform E). These results are discussed in relation to in situ AMP deaminase activity in neonatal piglet heart myocytes.
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PMID:Isolation and regulation of piglet cardiac AMP deaminase. 1063 Jun 34

AMPD (AMP deaminase), an enzyme catalyzing AMP to IMP, plays an important role in purine/urate metabolism. AMPD is encoded in 3 genes for 3 isozymes M, L and E (H), respectively. In humans, 2 AMPD deficiencies have been reported in skeletal muscles (AMPD1 deficiency) and red blood cells (AMPD3 deficiency). AMPD1 deficiency has been found in patients with metabolic myopathy. AMPD regulates important purine nucleotides including ATP, ADP, AMP, IMP et al. Also, AMPD deficiency may change the level of adenosine, an important bioactive molecule. In addition, AMP activated protein kinase (AMPK) activity, controlled by intracellular AMP, has an important role as an energy sensor. Therefore, AMPD may control the systemic metabolic status by changing AMPK activity through the AMP level.
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PMID:[AMPD genes and urate metabolism]. 1840 30

AMP deaminase (AMPD) catalyzes AMP to IMP and plays an important role in energy charge and nucleotide metabolism. Human AMPD3 deficiency is a type of erythrocyte-specific enzyme deficiency found in individuals without clinical symptoms, although an increased level of ATP in erythrocytes has been reported. To better understand the physiological and pathological roles of AMPD3 deficiency, we established a line of AMPD3-deficient [A3(-/-)] mice. No AMPD activity and a high level of ATP were observed in erythrocytes of these mice, similar to human RBC-AMPD3 deficiency, while other characteristics were unremarkable. Next, we created AMPD3 and pyruvate kinase (PK) double-deficient [PKA(-/-,-/-)] mice by mating A3(-/-) mice with CBA-Pk-1slc/Pk-1slc mice [PK(-/-)], a spontaneous PK-deficient strain showing hemolytic anemia. In PKA(-/-,-/-) mice, the level of ATP in red blood cells was increased 1.5 times as compared to PK(-/-) mice, although hemolytic anemia in those animals was not improved. In addition, we observed osmotic fragility of erythrocytes in A3(-/-) mice under fasting conditions. In contrast, the ATP level in erythrocytes was elevated in A3(-/-) mice as compared to the control. In conclusion, AMPD3 deficiency increases the level of ATP in erythrocytes, but does not improve anemia due to PK deficiency and leads to erythrocyte dysfunction.
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PMID:AMPD3-deficient mice exhibit increased erythrocyte ATP levels but anemia not improved due to PK deficiency. 2307 45

Nucleotide metabolism and signalling is directly linked to myocardial function. Therefore analysis how diversity of genes coding nucleotide metabolism related proteins affects clinical progress of heart disease could provide valuable information for development of new treatments. Several studies identified that polymorphism of AMP deaminase 1 gene (AMPD1), in particular the common C34T variant of this gene was found to benefit patients with heart failure and ischemic heart disease. However, these findings were inconsistent in subsequent studies. This prompted our detailed analysis of heart transplant recipients that revealed diverse effect: improved early postoperative cardiac function associated with C34T mutation in donors, but worse 1-year survival. Our other studies on the metabolic impact of AMPD1 C34T mutation revealed decrease in AMPD activity, increased production of adenosine and de-inhibition of AMP regulated protein kinase. Thus, genetic, clinical and biochemical studies revealed that while long term attenuation of AMPD activity could be deleterious, transient inhibition of AMPD activity before acute cardiac injury is protective. We suggest therefore that pharmacological inhibition of AMP deaminase before transient ischemic event such as during ischemic heart disease or cardiac surgery could provide therapeutic benefit.
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PMID:AMP deaminase 1 gene polymorphism and heart disease-a genetic association that highlights new treatment. 2443 Oct 31

AMP deaminase (AMPD; EC 3.5.4.6) catalyzes hydrolysis of the amino group from the adenine ring of AMP resulting in production of inosine 5'-monophosphate (IMP) and ammonia. This reaction helps to maintain healthy cellular energetics by removing excess AMP that accumulates in energy depleted cells. Furthermore, AMPD permits the synthesis of guanine nucleotides from the larger adenylate pool. This enzyme competes with cytosolic 5'-nucleotidases (c5NT) for AMP. Adenosine, a product of c5NT is a vasodilator, antagonizes inotropic effects of catecholamines and exerts anti-platelet, anti-inflammatory and immunosuppressive activities. The ratio of AMPD/c5NT defines the amount of adenosine produced in adenine nucleotide catabolic pathway. Inhibition of AMPD could alter this ratio resulting in increased adenosine production. Besides the potential effect on adenosine production, elevation of AMP due to inhibition of AMPD could also lead to activation of AMP regulated protein kinase (AMPK) with myriad of downstream events including enhanced energetic metabolism, mitochondrial biogenesis and cytoprotection. While the benefits of these processes are well appreciated in cells such as skeletal or cardiac myocytes its role in protection of endothelium could be even more important. Therapeutic use of AMPD inhibition has been limited due to difficulties with obtaining compounds with adequate characteristics. However, endothelium seems to be the easiest target as effective inhibition of AMPD could be achieved at much lower concentration than in the other types of cells. New generation of AMPD inhibitors has recently been established and its testing in context of endothelial and organ protection could provide important basic knowledge and potential therapeutic tools.
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PMID:Inhibition of AMP deaminase as therapeutic target in cardiovascular pathology. 2632 Dec 68

Hibernation is an important winter survival strategy for many small mammals. By sinking into a deep torpor where metabolic rate can be as low as 1-5% of the resting rate in euthermia, animals accrue huge energy savings that allow survival, typically without eating, for many months. Hibernating ground squirrels show a net reduction in the total adenylate pool of skeletal muscle during torpor, but the ATP/ADP ratio and adenylate energy charge remain stable. A key enzyme involved in managing adenylate pool size is 5'-adenosine monophosphate deaminase (AMPD). Assessing skeletal muscle AMPD from both Richardson's ground squirrels (Urocitellus richardsonii) (RGS) and 13-lined ground squirrels (Ictidomys tridecemlineatus) (TLGS), the present study shows that muscle AMPD of euthermic versus hibernating animals displays markedly different kinetic properties, differential responses to temperature and to effectors, and is regulated by reversible protein phosphorylation. AMPD activity decreased during hibernation in both TLGS and RGS skeletal muscle, by 70 and 84%, respectively. Stimulation of total protein phosphatases, total serine/threonine protein phosphatases, PP1, PP2B or PP2C, all reduced AMPD activity between 54 and 92% in extracts of euthermic RGS muscle. The same incubation did not change the activity of AMPD from muscle of hibernating animals. Oppositely, both euthermic and hibernating AMPD showed a strong increase in activity when incubated under conditions that promoted the enzyme phosphorylation by PKA, PKC or PKG. Overall, the data indicate that both low activity of AMPD and low affinity of the enzyme for AMP during torpor reduce the rate of adenylate degradation, the primary driver of these changes being covalent phosphorylation of AMPD.
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PMID:5'-Adenosine monophosphate deaminase regulation in ground squirrels during hibernation. 3330 76