Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During diauxic growth of yeast in glucose-rich medium, the accumulation of trehalose started well after complete exhaustion of glucose from the medium. The accumulation of the disaccharide was concomitant with a resumption of cell growth on the ethanol accumulated in the medium, but not with a degradation of glycogen which occurred as soon as glucose had been consumed. In contrast, in a mutant deficient in phosphoenolpyruvate carboxykinase, the synthesis of trehalose coincided exactly with the degradation of glycogen. Upon inoculation of stationary phase wild-type cells into a glucose medium, the activities of trehalose-6-phosphate (Tre6P) synthase and Tre6P phosphatase dropped in parallel to reach only 15% of their initial values after 3 h, and only recovered their original values as cells re-entered stationary phase. In the presence of cycloheximide, the decrease in Tre6P synthase and Tre6P phosphatase activities was restricted to 50-60%, the remaining decrease being inhibited by the drug. Furthermore, the reappearance of the enzyme activities following transfer of cells to an acetate medium was blocked by cycloheximide. It was also shown that loss of activity of these two enzymes required a combination of metabolizable sugars together with a nitrogen source. Low activities of Tre6P synthase and Tre6P phosphatase were measured in mutants with increased adenylate cyclase activity (RAS2ala18val19 mutants). Moreover, derepression of these enzymes at the approach of stationary phase was prevented in a pde2 mutant when it was cultivated in the presence of exogenous cyclic nucleotide. The mechanism of this effect is not clear, but may involve a transcriptional regulation by cAMP of the genes encoding these proteins.
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PMID:The control of trehalose biosynthesis in Saccharomyces cerevisiae: evidence for a catabolite inactivation and repression of trehalose-6-phosphate synthase and trehalose-6-phosphate phosphatase. 166 49

To explain mechanisms responsible for derangement of insulin release in uremia, we investigated glucose metabolism through three different tests in 14 patients with end-stage chronic renal failure. These tests were: intravenous glucose tolerance test with 0.33 g/kg of glucose solution (IVGTT); IVGTT with 0.5 g/kg of glucose solution (IVGTT2); IVGTT during aminophylline infusion (IVGTT + A). Twelve of the patients had IVGTT repeated after two to four months of thrice-weekly regular hemodialysis (IVGTT3). In each test we measured plasma glucose (G), immunoreactive insulin (IRI) and C-peptide. We also calculated glucose constant decay (K), insulin production (IRI area), insulinogenic index (IGI), and insulin resistance index (RI). Twenty-nine healthy volunteers formed the normal controls for IVGTT. As compared to controls, during IVGTT uremic patients showed significantly lower values in K, IRI area and IGI, and showed a significant RI value increase. During IVGTT2, IRI are values were higher than during IVGTT but IGI and K values were unchanged. During IVGTT + A both IRI area and IGI values were higher than during IVGTT. After hemodialysis treatment (IVGTT3) K, IRI areas and IGI increased significantly as compared to the predialysis period. K increase after hemodialysis correlated directly to IGI increase and inversely to RI changes. IGI increase during IVGTT3 was directly correlated to IGI rise during IVGTT + A. From these data we infer that defective insulin release in uremia is due to a decrease of beta-cell glucose sensitivity rather than to their functional exhaustion. An impaired adenyl cyclase-cAMP system may have an important role in the pathogenesis of this abnormality.
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PMID:Glucose-induced insulin secretion in uremia: effects of aminophylline infusion and glucose loads. 196 48

Saccharomyces cerevisiae contains two RAS genes, RAS1 and RAS2. An insertion mutation in RAS2 (ras2::LEU2) does not affect growth on glucose based media but it does prevent growth on media with pyruvate or other noncarbohydrate carbon sources. This defect is pH sensitive and is most severe at pH 7 and above. The ras2::LEU2 mutation also causes markedly higher levels of glycogen in the derepressed phase of growth after glucose exhaustion. Selection for restoration of growth on pyruvate yields unlinked suppressor mutations. Some of the suppressors also reduce glycogen as well as trehalose (the other reserve carbohydrate in yeast) to levels much lower than those of wild-type strains. These suppressor mutations do not suppress the lethality of ras1 ras2 double mutants. The results indirectly accord with yeast RAS2 governing a G protein activity of adenylate cyclase.
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PMID:On ras gene function in yeast. 389 24

Measurements of adenosine 3':5'-cyclic monophosphate (cAMP) concentrations have been made in Escherichia coli under various conditions. Different strains of E. coli accumulate different extracellular concentrations of cAMP (0.2-4 mum) at stationary phase. Mutation at the RNA control locus does not affect the accumulation pattern. Growth of the bacteria in minimalsalts medium leads to a greater accumulation of cAMP than growth in nutrient broth. Partition studies show that essentially all of the cAMP that is accumulated is found in the medium rather than in the cells. Kinetic studies show that most of the cAMP is formed coincidentally with exhaustion of glucose from the medium. Growth on high concentrations of glucose leads to inhibition of cAMP formation. Other carbon sources cannot substitute for glucose in this inhibitory effect. Measurements of enzyme activities indicate that glucose suppression of cAMP formation cannot be accounted for by a decreased activity of adenylate cyclase or an increased activity of cAMP phosphodiesterase (EC 3.1.3.7).
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PMID:Glucose and the metabolism of adenosine 3':5'-cyclic monophosphate in Escherichia coli. 433 Sep 42

Recently, it has been suggested that epinephrine influences blood lactate and the lactate threshold during incremental exercise through a beta-adrenergic adenylate cyclase dependent mechanism. We sought to characterize the relationship between the changes in the beta-adrenergic adenylate cyclase system and blood lactate during incremental exercise indirectly through the measurement of plasma cAMP. The relationships of plasma cAMP to blood lactate levels and the lactate threshold were examined in nine untrained male subjects. Each subject performed an incremental exercise test to volitional exhaustion on an electronically-braked cycle ergometer. Although plasma cAMP was rising at the lactate threshold, it did not demonstrate the classic threshold response usually seen in blood lactate. Pairwise matched t-tests were used as a post-hoc test to determine if the successive changes in blood lactate and plasma cAMP between 21.4, 38.6, 58.7, 81.2 and 100% of VO2max were significant. Plasma cAMP was rising between 38.6% and 58.7% and between 58.7% and 81.2% of VO2max, but these changes in plasma cAMP did not reach statistical significance (p > 0.0125) with Bonferoni adjustment. The change in plasma cAMP compared to its previous value as well as the change in plasma cAMP above the resting value was not statistically significant until 81.2% of VO2max. A moderate but significant correlation was observed between blood lactate and plasma cAMP levels (r = 0.612) using blood samples obtained at each workstage in all subjects. The mean correlation between blood lactate and plasma cAMP was 0.75 (S.E. = 0.05) and ranged between 0.58 and 0.97 in individual subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Plasma cyclic AMP and blood lactate responses to incremental cycling in untrained male subjects. 824 1

The basic mechanisms of regulation of Ca2+ influx in proliferating and differentiating myoblasts, in culture have been studied. The presence of L-type Ca2+ channels in proliferating myoblasts has been shown for the first time. The influx of Ca2+ through these channels was shown to be regulated by the adrenergic system. The influx of Ca2+ through L-type Ca2+ channels after the activation of the adrenergic system by the addition of adrenaline in comparison with the contribution of reticular stocks exhausted by ATP in calcium-free medium was estimated. It was shown that the Ca2+ influx in proliferating myoblasts is regulated by beta-2 adrenergic receptors whose action is mediated by adenylate cyclase through L-type calcium channels. In differentiating myoblasts, the Ca2+ influx on the activation of the adrenergic system was essentially lower than in proliferating cells. It was found that the maximum influx of Ca2+ may be reached by the exhaustion of reticular stocks.
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PMID:[Regulation of Ca2+ influx in proliferating and differentiating myoblasts of mice with participation of L-type Ca2+ channels]. 2144 87

Malignant cells acquire physiological mechanisms of immunosuppression to escape immune surveillance. Strategies to counteract this suppression could help to improve adoptive immunotherapy regimen. The intracellular second messenger cyclic AMP (cAMP) acts as a potent immunosuppressive signaling molecule in T-cells and is up-regulated by multiple tumor-relevant suppressive factors including prostaglandin E2 (PGE2), adenosine and the functions of regulatory T-cells. Consequently, we aimed to abrogate cAMP signaling in human T-cells by ectopic overexpression of phosphodiesterase 4A (PDE4A). We could show that retroviral transduction of PDE4A into T-cells led to efficient degradation of cAMP in response to induction of adenylate cyclase. Retroviral transduction of PDE4A into CD4+ and CD8+ T-cells restored proliferation, cytokine secretion as well as cytotoxicity under immunosuppression by PGE2 and A2A-R agonists. PDE4A-transgenic T-cells were also partially protected from suppression by regulatory T-cells. Furthermore, PGE2-mediated upregulation of the inhibitory surface markers CD73 and CD94 on CD8+ T-cells was efficiently counteracted by PDE4A. Importantly, no differences in the functionality under non-suppressive conditions between PDE4A- and control-vector transduced T-cells were observed, indicating that PDE4A does not interfere with T-cell activation per se. Similarly, expression of surface markers associated with T-cell exhaustion were not influenced by PDE4A overexpression in long term cultures. Thus, we provide first in vitro evidence that PDE4A can be exploited as immune checkpoint inhibitor against multiple suppressive factors.
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PMID:Overexpression of PDE4A Acts as Checkpoint Inhibitor Against cAMP-Mediated Immunosuppression in vitro. 3141 63