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:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work from this laboratory has demonstrated that 25(OH) vitamin D3 [25(OH)D3] acutely suppresses the phosphaturic action of parathyroid hormone (PTH) and interferes with the PTH-induced activation of adenylate cyclase (AC). Calmodulin inhibitors block vitamin D-induced Ca2+ transport in the gut and phosphorus uptake in renal BBMV's. We have examined whether calmodulin antagonists affect the renal action of 25(OH)D3. Acute clearance experiments were performed in PTH-infused parathyroidectomized rats receiving 25(OH)D3 after pretreatment with trifluoperazine (TFP) or promethazine (P). In vitro PTH-induced activation of renal AC was also studied in membrane preparations from pretreated rats in the presence of 25(OH)D3. 25(OH)D3 reduced the PTH-stimulated increase in fractional excretion of phosphorus (CP/CIn) from 0.292 +/- 0.024 to 0.195 +/- 0.018 (p less than 0.005) and urinary cAMP from 149.3 +/- 20.3 to 78.1 +/- 10.4 pmol/min (p less than 0.01) and also blunted AC activation in vitro. TFP but not P abolished the effects of 25(OH)D3 both in vivo and in vitro. R 24571 also abolished the in vitro effect of 25(OH)D3. Thus, (1) TFP abolishes both the antiphosphaturic and the AC/cAMP-related actions of 25(OH)D3, (2) P does not have these effects, and (3) R 24571 abolishes the in vitro effect of 25(OH)D3. These results suggest that the antiphosphaturic effect of 25(OH)D3 acting via the AC/cAMP system may be calmodulin dependent.
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PMID:The in vivo and in vitro effect of calmodulin antagonists on the renal actions of 25(OH) vitamin D3 in the rat. 256 Jan 71

Studies on the pathogenesis of hypercalcemia in canine lymphosarcoma have led to conflicting results. The biochemical and bone histomorphometric findings in canine lymphosarcoma were examined in 19 hypercalcemic and 17 nonhypercalcemic dogs with lymphosarcoma. Compared to the nonhypercalcemic group, the hypercalcemic dogs demonstrated an increase in fasting and 24-h calcium excretion, an increase in fractional phosphorus excretion, and a significant increase in nephrogenous AMP excretion. Plasma 1,25-dihydroxyvitamin D and immunoreactive PTH levels were equivalent in the two groups. Quantitative bone histomorphometry performed on iliac crest biopsies revealed increased parameters of bone resorption in those hypercalcemic dogs with no evidence of tumor at the biopsy site, without a compensatory increase in bone formation. Acid-urea tumor tissue extracts from eight hypercalcemic and six nonhypercalcemic dogs were examined for adenylate cyclase-stimulating activity (ACSA). All tumors from hypercalcemic dogs contained ACSA, whereas none of the tumors from nonhypercalcemic dogs had ACSA. Further purification of one tumor extract yielded an adenylate cyclase-stimulating protein which appeared to interact specifically with the PTH receptor. We conclude that in some cases, hypercalcemia in canine lymphosarcoma is mediated by a tumor-derived circulating bone-resorbing factor which is distinct from PTH. ACSA detected in tumor tissue appears to be a reliable marker for the syndrome in vivo. The role of this activity in the pathogenesis of the syndrome remains to be determined.
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PMID:Humoral hypercalcemia of malignancy in canine lymphosarcoma. 282 6

Although more than 50 patients with the tumor-induced osteomalacia syndrome, characterized by remission of unexplained osteomalacia after resection of a coexisting tumor, have been reported, the pathogenesis of this syndrome is still not clear. We investigated the cause of biopsy-confirmed osteomalacia which was resistant to treatment with 1 alpha-hydroxyvitamin D3 in a 54-yr-old man. He had severe hypophosphatemia, a high serum alkaline phosphatase level, a low plasma 1,25-dihydroxyvitamin D level, and remarkably increased urinary phosphorus excretion. A tumor, with histological characteristics of a hemangiopericytoma, was found on his left thigh. After surgical removal of this tumor, his plasma 1,25-dihydroxyvitamin D and serum phosphorus levels increased to normal levels, and his bone pain subsided. The tumor was transplanted to athymic nude mice. A nodule formed in each mouse, with histological features identical to those of the original tumor, and the tumor-bearing mice had hypophosphatemia, high serum alkaline phosphatase levels, and increased urinary phosphorus excretion. When extracts of the original tumor were added to primary cultures of renal tubular cells, renal cAMP levels did not change, but 25-hydroxyvitamin D-1 alpha-hydroxylase activity was significantly inhibited. These data indicate tumoral production of some humoral factor(s) inhibiting 25-hydroxyvitamin D-1 alpha-hydroxylase activity and phosphorus reabsorption unrelated to adenylate cyclase-cAMP production in proximal renal tubules.
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PMID:Hemangiopericytoma-induced osteomalacia: tumor transplantation in nude mice causes hypophosphatemia and tumor extracts inhibit renal 25-hydroxyvitamin D 1-hydroxylase activity. 283

We examined the regulation of 1,25-dihydroxyvitamin D [1,25(OH)2D] synthesis in patients with hypoparathyroidism (n = 5) and pseudohypoparathyroidism (n = 5) by administration of parathyroid extract (PTE) and N6,O2-dibutyryladenosine 3',5'-cyclic monophosphate (dbcAMP) and by phosphorus deprivation with antacids. In response to PTE, patients with hypoparathyroidism increased serum 1,25(OH)2D from 17 +/- 5 to 30 +/- 5 (SD) pg/ml (P less than 0.01). An approximate doubling of the 1,25(OH)2D concentration also occurred following dbcAMP infusion or phosphorus deprivation (serum phosphorus 4.4 +/- 0.5 to 2.6 +/- 1.1, P less than 0.01). Serum phosphorus and 1,25(OH)2D concentrations were inversely correlated (r = -0.73, P less than 0.001). Patients with pseudohypoparathyroidism had negligible responses to PTE with respect to urinary adenosine 3', 5'-cyclic monophosphate excretion, serum phosphorus concentration, or 1,25(OH)2D synthesis. They did show a rise in serum 1,25(OH)2D from 17 +/- 4 to 44 +/- 5 pg/ml (P less than 0.001) in response to dbcAMP infusion. During phosphorus deprivation, serum phosphorus decreased from 4.1 +/- 0.8 to 3.2 +/- 1.2 mg/dl (P less than 0.05), but there was no change in serum 1,25(OH)2D concentration or any correlation between serum phosphorus and 1,25(OH)2D levels. Although reduction in mean serum phosphorus levels was generally not as great in patients with pseudohypoparathyroidism, one such patient attained serum phosphorus of 1.2 mg/dl and still did not increase serum 1,25(OH)2D concentration. In addition to an abnormal parathyroid hormone receptor-adenylate cyclase complex, patients with pseudohypoparathyroidism appear to have an abnormal renal 1 alpha-hydroxylase, which does not respond appropriately to phosphate deprivation.
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PMID:Regulation of 1,25 (OH)2D synthesis in hypoparathyroidism and pseudohypoparathyroidism. 284 40

Gentamicin nucleotidyltransferase-catalyzed reaction of (Sp)-[alpha-17O]dATP with tobramycin produced 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. The configuration at phosphorus in this product was shown to be Rp by chemical degradation to chiral [17O, 18O]dAMP using a stereochemically defined procedure, and determination of the configuration at phosphorus in this product. Periodate-base treatment of 2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin followed by NaBH4 reduction produced (2-glyceryl)-[17O]dAMP, which upon snake venom phosphodiesterase-catalyzed hydrolysis in H(2)18O produced [17O,18O] dAMP. The configuration at phosphorus in this product was shown to be S by enzymatic phosphorylation to [17O,18O]dATP, adenylylcyclase (Bordetella pertussis)-catalyzed cyclization to 3',5'-cyclic [17O,18O]dAMP, and 31P NMR analysis of the ethyl esters. Since snake venom phosphodiesterase-catalyzed hydrolyses proceed with retention of configuration at phosphorus, (Sp)-[17O,18O]dAMP must have been produced from (Rp)-(2-glyceryl)-[17O]dAMP; and since the chemical degradation to the latter compound did not involve cleavage of any bonds to phosphorus, the initial enzymatic product must have been (Rp)-2"-(2'-deoxyadenosine 5'-[17O]phosphoryl)tobramycin. Therefore, nucleotidyl transfer catalyzed by gentamicin nucleotidyl-transferase proceeds with inversion of configuration at phosphorus, and the reaction mechanism involves an uneven number of phosphotransfer steps. Inasmuch as this is an uncomplicated two-substrate group transfer reaction, the mechanism probably involves direct nucleotidyl transfer from the nucleoside triphosphate to the aminoglycoside. The B. pertussis adenylylcyclase reaction was shown to proceed with inversion at phosphorus, as has been established for other adenylylcyclases.
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PMID:Gentamicin nucleotidyltransferase. Stereochemical inversion at phosphorus in enzymatic 2'-deoxyadenylyl transfer to tobramycin. 287 83

The present studies examine the initial events in the action of PTH, namely receptor binding and adenylate cyclase activation in the postobstructed canine kidney. Both kidneys were removed from five mongrel dogs 2 h after relief of unilateral ureteral obstruction (UUO) of 42 h duration. Basolateral membranes (BLM) were prepared from both the UUO and contralateral (control) kidneys. Maximal activation of adenylate cyclase by PTH was 35% lower (P less than 0.01) in BLM from UUO than control kidneys (3869 +/- 200 vs. 5978 +/- 425 pmol cAMP/mg protein X 30 min). The concentration of PTH required for half-maximal activation of the enzyme was unchanged. Addition of 1 mM GTP failed to correct the decreased enzyme activity in response to PTH of BLM from kidneys with UUO. NaF activation, a measure of interaction of the nucleotide regulatory component (G/F) with the catalytic unit of the adenylate cyclase was similar in BLM from UUO and control kidneys. Similarly, activation of the catalytic unit of the enzyme by Mn2+ was not different. Specific binding of [125I]Nle8, Nle8, Tyr34-bovine PTH NH2 was markedly reduced (P less than 0.01) in BLM from UUO vs. control (6.37 +/- 1.20 vs. 2.43 +/- 0.09 fmole bound/microgram protein). There was no change in hormone affinity for the binding site. These data indicate that there is decreased activation of adenylate cyclase by PTH as a consequence of apparent loss of receptors for the hormone in the BLMs of renal tubular cells of postobstructed kidneys. These abnormalities may play a role in the abnormal regulation of phosphorus excretion after ureteral obstruction.
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PMID:Impaired parathyroid hormone receptor-adenylate cyclase system in the postobstructed canine kidney. 298 70

Adenylate cyclase activity in particulate preparations of ovarian tumors from 47 women was determined by measuring the conversion of phosphorus 32-labeled adenosine triphosphate to phosphorus 32-labeled cyclic adenosine monophosphate. Ovarian cancers typically exhibited an active adenylate cyclase which was stimulated by 50 mumol/L 5'-guanylylimidodiphosphate and 10 mmol/L of sodium fluoride. This activity was comparable to that in particulates of normal postmenopausal ovaries and was independent of the class of tumor. There was no significant increase in adenylate cyclase activity in any epithelial or germinal tumor in the presence of either 250 nmol/L of human chorionic gonadotropin or 333 nmol/L human follicle-stimulating hormone. However, cyclic adenosine monophosphate production by two sex cord stromal tumors was stimulated by follicle-stimulating hormone, but not by human chorionic gonadotropin. Follicle-stimulating hormone stimulated a threefold increase in activity in the granulosa-theca cell tumor, with an activation constant (57 nmol/L) similar to that in follicle-stimulating hormone-responsive rat ovaries. Prostaglandin E1 (50 mumol/L) increased cyclic adenosine monophosphate production by epithelial tumors more than twofold. These data suggest that sex cord stromal tumors, unlike the more common epithelial tumors, can be modulated directly by gonadotropin.
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PMID:Adenylate cyclase in human ovarian cancers: sensitivity to gonadotropins and nonhormonal activators. 300 Jan 83

Improved management of peptic ulcer disease requires elucidation of cellular processes underlying gastric secretion. The intracellular execution of regulatory commands to secretory cells involves protein phosphorylation. We studied cyclic adenosine monophosphate (cAMP)-dependent phosphorylation in isolated gastric glands (IGGs) using forskolin, which directly stimulates adenylate cyclase. Forskolin stimulated secretion by both parietal and chief cells. In a separate set of studies, IGGs were incubated for 45, 90, and 105 minutes in modified Ham's F-10 medium containing orthophosphate labeled with phosphorus 32. The forskolin (10(-4) M) was added to some IGG preparations at 90 minutes. The reaction was terminated with sodium dodecyl sulfate and boiling. The proteins were resolved on sodium dodecyl sulfate-polyacrylamide gels, stained with Coomassie blue, and autoradiographed. Incorporation of phosphorus 32 increased progressively at 45, 90, and 105 minutes. Forskolin enhanced phosphorylated bands around 92 kilodaltons. These results are consistent with the major role of cAMP in the regulation of gastric cellular function. The study of cAMP-stimulated phosphorylation may be an important tool in the elucidation of intracellular regulatory mechanisms of gastric secretion. Modulation of these mechanisms may be the ideal therapeutic modality for treatment of acid-secretory disorders.
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PMID:Forskolin (cyclic adenosine monophosphate)-dependent protein phosphorylation in isolated gastric glands. 300 79

We have found that the cytochemical bioassay (CBA) method, originally developed to measure circulating levels of biologically active parathyroid hormone (bioPTH) in humans, also can measure endogenous concentrations of PTH in rats. Therefore, we have applied this assay method to examine the relationships between age and sex and the circulating levels of bioPTH, calcium, and phosphorus in Fischer rats. The concentration of bioPTH increased in both males and females from 5 to 15 months of age (p less than .001) with no significant sex-related difference. Mean bioPTH values ranged from 2.3 to 3.6 pg (human PTH equivalents)/ml; these values were much lower (1 to 2 orders-of-magnitude) than those reported by others who used radioimmunoassays for PTH that do not discriminate between biologically active and inert PTH fragments. The CBA values for bioPTH were also 1/4-1/5 those obtained in rat serum by newer, more sensitive methods, the N-terminal specific PTH radioimmunoassay and the bioassay based on stimulation of chick renal adenylate cyclase. Regression analysis did not reveal any significant correlation between serum calcium and age. However, serum inorganic phosphorus decreased significantly (p less than .001) from 5 to 15 months of age in both male and female rats and was much lower in females than in males (p less than .001). The fall in serum phosphorus was negatively correlated with the rise in bioPTH (p less than .001). This study, the first to our knowledge to use a CBA to detect physiological changes in the circulating levels of bioPTH in rats, demonstrates the usefulness of the assay in experiments in this species.
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PMID:Cytochemical bioassay of circulating concentrations of rat parathyroid hormone: application to a study of age and sex. 350 48

Peptides corresponding to the amino-terminal region of the parathyroid hormone-related protein (PTHrP) of humoral hypercalcemia of malignancy were synthesized. A 34-amino acid peptide, PTHrP(1-34), was two to four times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of adenosine 3',5'-monophosphate (cAMP) and plasminogen activator activity in osteogenic sarcoma cells and adenylate cyclase activity in chick kidney membranes. Like parathyroid hormone itself, in which the activity resides in the first 34 residues, PTHrP peptides of less than 30 residues from the amino terminus showed substantially reduced activity. PTHrP(1-34) had only 6% of the potency of bovine PTH(1-34) in promoting bone resorption in vitro. PTHrP(1-34) strongly promoted the excretion of cAMP and phosphorus and reduced the excretion of calcium in the isolated, perfused rat kidney consistent with the symptoms seen in malignant hypercalcemia.
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PMID:Parathyroid hormone-related protein of malignancy: active synthetic fragments. 368 95


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