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)

The diverse effects of the catecholamines (CA), epinephrine and norepinephrine, are mediated by a family of specific receptors (adrenergic receptors, AR). The beta-AR is a glycoprotein present in the membrane of a number of cell types. This receptor is closely associated with at least two other proteins, guanine nucleotide stimulating protein (Gs) and adenylate cyclase enzyme (AC), to form the beta-AR complex. The beta-AR recognizes the CA and is coupled to Gs which stimulates the effector enzyme AC. This enzyme converts ATP to cAMP and is the effector of the beta-AR complex. Thus the beta-AR is a G-coupled receptor which acts by raising intracellular levels of cAMP. The beta-AR is an important site of regulatory modifications through a variety of mechanisms. The best characterized is known as homologous desensitization: when the receptor is exposed to repeated stimuli by the agonist (CA), its responsiveness wanes, probably to compensate this potentially dangerous overstimulation. The gene for mammalian beta 2-AR has recently been cloned and the predicted amino acid sequence now opens the field to identification of the protein structures involved in receptor functions. The beta 2-AR protein is characterized by the presence of seven membrane spanning regions. The study of the structure, function and regulation of the beta-AR will extend our knowledge of the role of beta-AR in pathological conditions and suggest new therapeutic approaches.
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PMID:Advances on beta-adrenergic receptors. Molecular structure and functional regulation. 255 43

We isolated mutants defective in aggregation (aggregation-less) by mutagenizing the "double-bypass" mutant HG592 of Dictyostelium discoideum as the parental strain. One of the mutants expressed the contact site A glycoprotein with an apparent molecular weight of 80 X 10(3) on the cell surface in the normal developmental stage and retained EDTA-stable cell contact as well as EDTA-sensitive cell contact. However, the mutant failed to aggregate on agar plates with bacteria. This mutant was designated HG700. We could not identify any differences between this mutant and the parental strain in levels of adenylate cyclase or extracellular phosphodiesterase activity, or in its chemotaxis toward cAMP. The mutant had greatly decreased the incorporation of [35S] sulfate into the particulate fractions of the cells starved for 6 h. This suggests that the modification by sulfation may crucially affect the mechanism of cell aggregation.
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PMID:Isolation of an aggregation-less mutant of Dictyostelium discoideum with the expression of contact site A glycoprotein. 255 15

The small proteoglycans (PG) of bone consist of two different molecular species: one containing one chondroitin sulfate chain (PG II) and the other, two chains (PG I). These two proteoglycans are found in many connective tissues and have Mr = 45,000 core proteins with clear differences in their NH2-terminal sequences. Using antisera produced against synthetic peptides derived from the human PG I and PG II NH2 termini, we have isolated several cDNA clones from a lambda gt11 expression library made against mRNA isolated from human bone-derived cells. The clones, which reacted with antisera to the PG II peptide, were sequenced and found to be identical with the PG II class of proteoglycan from human fibroblasts known as PG-40 or decorin. The clones reacting to the PG I antisera, however, had a unique sequence. The derived protein sequence of PG I showed sufficient homology with the PG II sequence (55% of the amino acids are identical, with most others involving chemically similar amino acid substitutions) to strongly suggest that the two proteins were the result of a gene duplication. PG II (decorin) contains one attached glycosaminoglycan chain, while PG I probably contains two chains. For this reason, we suggest that PG I be called biglycan. The biglycan protein sequence contains 368 residues (Mr = 42,510 for the complete sequence and Mr = 37,983 for the secreted form) that appears to consist predominantly of a series of 12 tandem repeats of 24 residues. The repeats are recognized by their conserved leucines (and leucine-like amino acids) in positions previously reported for a diverse collection of proteins (none of which is thought to be proteoglycans) including: two morphogenic proteins (toll and chaoptin) in the fruit fly; a yeast adenylate cyclase; and two human proteins, the von Willebrand Factor-binding platelet membrane protein, GPIb, and a rare serum protein, leucine-rich glycoprotein.
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PMID:Deduced protein sequence of bone small proteoglycan I (biglycan) shows homology with proteoglycan II (decorin) and several nonconnective tissue proteins in a variety of species. 264 39

The responsiveness of enterocytes to Escherichia coli heat-labile enterotoxin (LT) was studied in the small intestine of 6- to 7-week-old rats. Dose-effect analysis showed the dose required for a 50% maximal LT-induced secretory response to be at 8 nM. After the well-documented glycolipid GM1 receptor was blocked with the cholera toxin B subunit, LT still activated the second messenger cascade, measured in terms of heightened cellular adenylate cyclase activity, and caused fluid to be secreted into ligated intestinal loops. Furthermore, Scatchard analysis of binding kinetics suggested that LT bound to two receptor sites on the intestinal microvillus membrane. The toxin also bound to delipidated membrane but was competitively inhibited by a galactose-specific lectin, RCA60, suggesting that the additional receptor is a galactoglycoprotein. Western blot analysis of toxin binding to membrane proteins revealed a group of binding components around 85 to 150 kilodaltons. When measured at 2.2 nM LT, approximately 70% of LT-binding activity took place through a high-affinity (Kd1, 0.38 nM) GM1 receptor and 30% of LT-binding activity took place through a low-affinity (Kd2, 3.3 nM) glycoprotein receptor. These results suggest that LT functions through two microvillus membrane receptors in the mature rat small intestine.
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PMID:Host response to Escherichia coli heat-labile enterotoxin via two microvillus membrane receptors in the rat intestine. 267 13

Covalent labeling of the canine renal parathyroid hormone receptor with [125I]bPTH(1-34) reveals several major binding components that display characteristics consistent with a physiologically relevant adenylate cyclase linked receptor. Through the use of the specific glycosidases neuraminidase and endoglycosidase F and affinity chromatography on lectin-agarose gels, we show here that the receptor is a glycoprotein that contains several complex N-linked carbohydrate chains consisting of terminal sialic acid and penultimate galactose in a beta 1,4 linkage to N-acetyl-D-glucosamine. No high mannose chains or O-linked glycans appear to be present. The peptide molecular weight of the deglycosylated labeled receptor is 62,000 [or 58,000 if the mass of bPTH(1-34) is excluded]. The binding of [125I]bPTH(1-34) to the receptor is inhibited in a dose-dependent fashion by wheat-germ agglutinin, but not by either succinylated wheat-germ agglutinin or Ricinus communis lectin, suggesting that terminal sialic acid may be involved in agonist binding. A combination of lectin affinity chromatography and immunoaffinity chromatography affords a 200-fold purification of the covalently labeled receptor.
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PMID:The canine renal parathyroid hormone receptor is a glycoprotein: characterization and partial purification. 282 60

The regulatory properties of adenylate cyclase in small intestinal mucosa were investigated. Glucagon, epinephrine and isoproterenol failed to activate the cAMP synthesis; prostaglandin E1 caused a 2.8-fold, while cholera toxin-a 4.5-fold stimulation. The latter was not able to increase the rate of glucose synthesis from alanine in vitro, but increased markedly the in vivo incorporation of 14C-labeled alanine into the mucus glucosamine. Unlabeled glucosamine excretion was also enhanced 3-fold. This provides evidence for the involvement of glycolysis and gluconeogenesis enzyme systems in the mucosal glycoprotein synthesis. It was assumed that both metabolic pathways may play a common physiological role, namely, to convert carbohydrates and gluconeogenic precursors into the substrate for glucosamine synthesis which is thought to be a rate-limiting step in small intestinal mucus secretion.
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PMID:[Relation between glycoprotein synthesis and carbohydrate metabolism in the small intestine mucosa. Effect of cholera enterotoxin]. 283 Sep 17

Vasoactive intestinal peptide (VIP) is a neuropeptide with a broad range of biological activities in various tissues. After interaction with its membrane receptor, VIP generally induces a very large increase in the intracellular cyclic AMP level. Receptors for VIP have been described in numerous tissues and cell lines. The first results on VIP receptor structure have been obtained by covalent cross-linking using bifunctional reagents. The molecular mass of the different components characterized in this way differs greatly according to the species and the tissue used. This heterogeneity may reflect either a difference in the length of the cross-linked polypeptide backbone or differently glycosylated forms of the same polypeptide. The VIP binding site of intact human adenocarcinoma cells (HT29 cells) is an Mr 64,000 glycoprotein with 20kDa of N-linked oligosaccharide side chains containing sialic acid. The structure of the VIP binding site from HT29 cell is compared, first to the structure of the VIP receptor from other tissues, particularly that from rat liver, and second to the structure of the hepatic glucagon binding site. Recently, solubilization of the VIP receptor in an active form has provided a new way of studying this receptor. The HT29 cell line is an appropriate model to study the dynamics of the VIP receptor. After binding to its receptor, VIP is rapidly internalized, probably by receptor-mediated endocytosis. This internalization leads to a decrease in the cell surface receptor number and simultaneously to a homologous desensitization of adenylate cyclase. VIP is then degraded in the lysosomes, while most of the receptors are recycled back to the cell surface. The presence of an intracellular pool of unoccupied VIP receptors has been demonstrated after inactivation of the cell surface receptors by chymotrypsin. The kinetics of the receptor reappearance at the cell surface, after inactivation by chymotrypsin or after receptor-mediated endocytosis, indicate 2 possible intracellular pathways for occupied and unoccupied VIP receptors.
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PMID:The vasoactive intestinal peptide (VIP) receptor: recent data and hypothesis. 285 63

Prostaglandin E2 (PGE2) specifically bound to 100,000 X g pellet prepared from bovine adrenal medulla, and [3H]PGE2-bound proteins were solubilized with 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid. The dissociation of bound [3H]PGE2 from the proteins was enhanced by GTP. [3H]PGE2-specifically bound proteins were adsorbed onto a wheat germ agglutinin column and GTP treatment decreased the amount of [3H]PGE2 retained on the column. When [3H]PGE2-bound proteins were cross-linked in the membrane by dithiobis(succinimidyl propionate) and solubilized, bound [3H]PGE2 was no longer dissociated by GTP treatment, suggesting that cross-linking produced a stable and high-affinity complex of PGE receptor with a GTP-binding protein. Covalent cross-linking of the complex was attested by adsorption of dithiobis(succinimidyl propionate)-treated [3H]PGE2-bound proteins to GTP-Sepharose, and co-elution of [35S]guanosine 5'-O-(3-thiotriphosphate) binding activity and immunoreactivities of alpha o and beta subunits of a GTP-binding protein. The cross-linked [3H]PGE2-bound complex was eluted as an apparently single radioactive peak at the position of Mr = 200,000 by gel filtration. These results have demonstrated that PGE receptor is a glycoprotein with an approximate Mr of 110,000, assuming that the Mr of the GTP-binding protein is 90,000. PGE2 neither activated nor inhibited adenylate cyclase activity, and pertussis toxin (islet-activating protein) did not affect PGE2 binding and its GTP sensitivity. These results suggest that the PGE receptor may be functionally associated with a pertussis toxin-insensitive GTP-binding protein and is not coupled to the adenylate cyclase system in bovine adrenal medulla.
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PMID:Covalent cross-linking of prostaglandin E receptor from bovine adrenal medulla with a pertussis toxin-insensitive guanine nucleotide-binding protein. 288 64

Somatostatin binding and cross-linking to its receptors on rat cerebrocortical membranes were characterized with [125I-Tyr1]somatostatin-14 and [125I-Leu8, D-Trp22, Tyr25]somatostatin-28. When [125I-Tyr1]somatostatin-14 was cross-linked to its receptors with the photoreactive cross-linker, N-(5-azido-2-nitrobenzoyloxy)succinimide, the hormone was specifically associated with a Mr = 72,000 protein band in the presence or absence of reducing agents. Affinity labeling of the Mr = 72,000 protein band was decreased with increasing concentrations of unlabeled somatostatin-14 and nonhydrolyzable guanine nucleotide analog, guanyl-5'-yl imidodiphosphate (Gpp(NH)p). Pretreatment of cerebrocortical membranes with islet-activating protein resulted in a decrease in subsequent labeled somatostatin-14 binding and affinity-labeling of the protein and abolished an inhibitory effect of somatostatin-14 on vasoactive intestinal peptide-stimulated increase in adenylate cyclase activity. When the affinity-labeled protein was solubilized with Zwittergent 3-12 and adsorbed to wheat germ agglutinin-agarose, it was eluted by N-acetylglucosamine. [125I-Leu8, D-Trp22, Tyr25]somatostatin-28 cross-linking to cerebrocortical and pancreatic membranes with the same photoreactive agent revealed specifically labeled protein bands of a Mr = 74,000 in cerebrocortical membranes and a Mr = 94,000 in pancreatic membranes, respectively. These results suggest that: 1) somatostatin receptor on cerebrocortical membranes is a monomeric glycoprotein with a Mr = 70,000 binding subunit, coupled to guanine nucleotide regulatory protein, and 2) the Mr = 70,000 protein may be a common receptor for somatostatin-28 and somatostatin-14 and is distinct from a common pancreatic type receptor.
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PMID:Somatostatin receptors on rat cerebrocortical membranes. Structural characterization of somatostatin-14 and somatostatin-28 receptors and comparison with pancreatic type receptors. 290 82

We have cloned CYR1, the S. cerevisiae gene encoding adenylate cyclase. The DNA sequence of CYR1 can encode a protein of 2026 amino acids. This protein would contain a central region comprised of over twenty copies of a 23 amino acid repeating unit with remarkable homology to a 24 amino acid tandem repeating unit of a trace human serum glycoprotein. Gene disruption and biochemical experiments indicate that the catalytic domain of adenylate cyclase resides in the carboxyl terminal 400 amino acids. Elevated expression of adenylate cyclase suppresses the lethality that otherwise results from loss of RAS gene function in yeast. Yeast adenylate cyclase, made in E. coli, cannot be activated by added RAS protein.
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PMID:DNA sequence and characterization of the S. cerevisiae gene encoding adenylate cyclase. 293 38


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