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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Guanylate cyclase (GTP pyrophosphate-lyase (cyclizing), EC 4.6.1.2) was purified 2250-fold from the synaptosomal soluble fraction of rat brain. The specific activity of the purified enzyme reached 41 nmol cyclic GMP formed per min per mg protein at 37 degrees C. In the purified preparation, GTPase activity was not detected and cyclic GMP phosphodiesterase activity was less than 4% of guanylate cyclase activity. The molecular weight was approx. 480 000. Lubrol PX, hydroxylamine, or NaN3 activated the guanylate cyclase in crude preparations, but had no effect on the purified enzyme. In contrast, NaN3 plus catalase, N-methyl-N'-nitro-N-nitrosoguanidine or sodium nitroprusside activated the purified enzyme. The purified enzyme required Mn2+ for its activity; the maximum activity was observed at 3-5 mM. Cyclic GMP activated guanylate cyclase activity 1.4-fold at 2 mM, whereas inorganic pyrophosphate inhibited it by about 50% at 0.2 mM. Guanylyl-(beta,gamma-methylene)-diphosphonate and guanylyl-imidodiphosphate, analogues of GTP, served as substrates of guanylate cyclase in the purified enzyme preparation. NaN3 plus catalase or N-methyl-N'-nitro-N-nitrosoguanidine also remarkably activated guanylate cyclase activity when the analogues of GTP were used as substrates.
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PMID:Purification and properties of guanylate cyclase from the synaptosomal soluble fraction of rat brain. 2 67

The activity of guanylate cyclase and that of its inhibitor present in E. coli extract, have been separated through a linear KCl gradient on DEAE-cellulose column. The activity of the inhibitor is lost after ribonuclease treatment, whereas is strengthened by addition of poly (C). Other types of RNA synthetic homopolymers do not affect the inhibitor's activity. Chromatographic analysis of the products of guanylate cyclase measured in the presence of FI and FI plus poly (C), indicated that the inhibitor has a poly (C) dependent GTPase activity.
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PMID:[Guanyl cyclase in Escherichia coli. II. Identification and characteristics on the enzyme inhibitor]. 3 98

We have been studying the mechanism by which light and nucleoside triphosphates activate the discmembrane phosphodiesterase (oligonucleate 5'-nucleotidohydrolase; EC 3.1.4.1) in frog rod outer segments. GTP is orders of magnitude more effective than ATP as a cofactor in the light-dependent activation step. GTP and the analogue guanylyl-imidodiphosphate function equally as allosteric activators of photoreceptor phosphodiesterase rather than participating in the formation of a phosphorylated activator. Moreover, we have found a light-activated (5-fold) GTPase which participates in the modulation of photoreceptor phosphodiesterase. This GTPase activity appears necessary for the reversal of phosphodiesterase activation in vitro and may play a critical role in the in vivo regulation of light-sensitive phosphodiesterase. The K(m) for GTP in the light-activated GTPase reaction is <1 muM. The light sensitivity of this GTPase (number of photons required for half-maximal activation) is identical to that of light-activated phosphodiesterase. The GTPase action spectrum corresponds to the absorption spectrum of rhodopsin. There is, in addition, a light-insensitive GTPase activity with a K(m) for GTP of 90 muM. At GTP concentrations above 5 muM, there is no appreciable activation of GTPase activity by light. The substrate K(m) values for guanylate cyclase, light-activated GTPase, and light-activated phosphodiesterase order an enzyme array that might permit light to simultaneously cause the hydrolysis of both the substrate and product of guanylate cyclase. These findings reveal yet another facet of light regulation of photoreceptor/cyclic GMP levels and also provide a striking analogy to the GTP regulation of nonphotoreceptor, hormone-sensitive adenylate cyclase.
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PMID:A light-activated GTPase in vertebrate photoreceptors: regulation of light-activated cyclic GMP phosphodiesterase. 20 Sep 9

Previous studies have demonstrated that the Dictyostelium G alpha subunit G alpha 2 is essential for the cAMP-activation of adenylyl cyclase and guanylyl cyclase and that g alpha 2 null mutants do not aggregate. In this manuscript, we extend the analysis of the function of G alpha 2 in regulating downstream effectors by examining the in vivo developmental and physiological phenotypes of both wild-type and g alpha 2 null cells carrying a series of mutant G alpha 2 subunits expressed from the cloned G alpha 2 promoter. Our results show that wild-type cells expressing G alpha 2 subunits carrying mutations G40V and Q208L in the highly conserved GAGESG (residues 38-43) and GGQRS (residues 206-210) domains, which are expected to reduce the intrinsic GTPase activity, are blocked in multicellular development. Analysis of down-stream effector pathways essential for mediating aggregation indicates that cAMP-mediated activation of guanylyl cyclase and phosphatidylinositol-phospholipase C (PI-PLC) is almost completely inhibited and that there is a substantial reduction of cAMP-mediated activation of adenylyl cyclase. Moreover, neither mutant G alpha 2 subunit can complement g alpha 2 null mutants. Expression of G alpha 2(G43V) and G alpha 2(G207V) have little or no effect on the effector pathways and can partially complement g alpha 2 null cells. Our results suggest a model in which the dominant negative phenotypes resulting from the expression of G alpha 2(G40V) and G alpha 2(Q208L) are due to a constitutive adaptation of the effectors through a G alpha 2-mediated pathway. Analysis of PI-PLC in g alpha 2 null mutants and in cell lines expressing mutant G alpha 2 proteins also strongly suggests that G alpha 2 is the G alpha subunit that directly activates PI-PLC during aggregation. Moreover, overexpression of wild-type G alpha 2 results in the ability to precociously activate guanylyl cyclase by cAMP in vegetative cells, suggesting that G alpha 2 may be rate limiting in the developmental regulation of guanylyl cyclase activation. In agreement with previous results, the activation of adenylyl cyclase, while requiring G alpha 2 function in vivo, does not appear to be directly carried out by the G alpha 2 subunit. Our data are consistent with adenylyl cyclase being directly activated by either another G alpha subunit or by beta gamma subunits released on activation of the G protein containing G alpha 2.
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PMID:Amino acid substitutions in the Dictyostelium G alpha subunit G alpha 2 produce dominant negative phenotypes and inhibit the activation of adenylyl cyclase, guanylyl cyclase, and phospholipase C. 135 76

Transmembrane signal transduction was investigated in four Dictyostelium discoideum mutants that belong to the fgd A complementation group. The results show the following. (a) Cell surface cAMP receptors are present in fgd A mutants, but cAMP does not induce any of the intracellular responses, including the activation of adenylate or guanylate cyclase and chemotaxis. (b) cAMP induces down-regulation and the covalent modification (presumably phosphorylation) of the cAMP receptor. (c) The inhibitory effects of GTP gamma S and GDP beta S on cAMP binding are reduced; the stimulatory effect of cAMP on GTP gamma S binding is lost in fgd A mutants. (d) Basal high-affinity GTPase activity is reduced 40% and the stimulatory effect of cAMP is decreased from 40% in wild type to 30% in fgd A. (e) GTP-mediated stimulation and inhibition of adenylate cyclase is normal in mutant membranes. The results suggest a defective interaction between cell surface cAMP receptors and a specific G-protein in fgd A mutants. This interaction appears to be essential for nearly all signal transduction pathways in Dictyostelium discoideum.
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PMID:Signal transduction in Dictyostelium fgd A mutants with a defective interaction between surface cAMP receptors and a GTP-binding regulatory protein. 284 45

The stability of dopamine-sensitive adenylate cyclase, guanylate cyclase, ATPase, and GTPase was measured in homogenates of rat striatal tissue frozen from 0 to 24 h postmortem. ATPase, GTPase, and Mg2+-dependent guanylate cyclase activities showed no significant change over this period. Mn2+-dependent guanylate cyclase activity was stable for 10 h postmortem. Basal and dopamine-stimulated adenylate cyclase activity decreased markedly during the first 5 h. However, when measured in washed membrane preparations, these adenylate cyclase activities remained stable for at least 10 h. Therefore, the postmortem loss of a soluble activator, such as GTP, may decrease the adenylate cyclase activity in homogenates. These results are not consistent with an earlier suggestion that there is a postmortem degradation of the enzyme itself. Other kinetic parameters of dopamine-sensitive adenylate cyclase can also be measured independently of postmortem changes. Thus, it is possible to investigate kinetic parameters of dopamine-sensitive adenylate cyclase, guanylate cyclase, ATPase, and GTPase in human brain obtained postmortem.
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PMID:Postmortem stability of dopamine-sensitive adenylate cyclase, guanylate cyclase, ATPase, and GTPase in rat striatum. 612 Sep 96

Levels of cGMP phosphodiesterase, guanylate cyclase, and GTPase activities were determined in homogenates of chick pineal glands. Only small variations in vivo were observed with glands removed at different times of the day from birds under a standard cycle of illumination. Glands cultured under the cycle of illumination from late in the photoperiod showed a progressive loss of about half the phosphodiesterase activity in 24 h, and an increase of roughly 75% in GTPase activity within 12 h. No simple correlations were found between variations in levels of enzyme activity and the diurnal cycles in pineal content of cGMP and level of serotonin N-acetyltransferase (NAT) activity. However, onset of rapid increases in 3',5'-cyclic GMP (cGMP) content and NAT activity was correlated with a transient decrease of about 30% in the phosphodiesterase activity, both in vivo and in culture. Further, known inhibitors of phosphodiesterase activity previously shown to elicit increase of cGMP content and marked elevation of NAT activity in cultured glands only inhibited phosphodiesterase activity of homogenates by 25-30%. It was therefore concluded that the transient decrease in level of phosphodiesterase may facilitate onset of increase in pineal cGMP content. However, it seems improbable that changes in pineal content of enzymes of guanine nucleotide metabolism are essential to regulation of diurnal cycles in cGMP content or level of NAT activity.
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PMID:Enzymes of guanine nucleotide metabolism and the diurnal cycle in cGMP content of the chick pineal gland. 613 5

hGBP1 is an interferon-induced 67-kDa protein of human cells that readily binds to agarose-immobilized GTP, GDP, and GMP but not to other nucleotides. We cloned hGBP1 cDNA into a histidine-tagging vector, produced recombinant hGBP1 with 6 extra histidine residues at its N terminus in Escherichia coli, and purified this protein to near homogeneity from bacterial lysates. Purified hGBP1 hydrolyzed radiolabeled GTP but failed to hydrolyze ATP, UTP, or CTP at significant rates. Unexpectedly, the principal product of the GTP hydrolysis reaction was GMP rather than GDP. Although significant amounts of GDP were produced when the reaction was performed at 15 degrees C, GDP could not serve as substrate or as inhibitor of hGBP1. hGBP1 lacked guanylate cyclase and guanylyltransferase activity. Degradation of GTP to GMP most likely occurred via two consecutive cleavages of single phosphate groups, because pyrophosphate was not a reaction product, and because hGBP1 failed to hydrolyze GTP gamma S. In vitro modification assays with radiolabeled mevalonic acid and farnesyl pyrophosphate showed that the CaaX motif at the C terminus of hGBP1 functions as an isoprenylation signal. Thus, hGBP1 is a GTPase with novel biochemical properties that may be membrane-associated in eukaryotic cells.
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PMID:The interferon-induced 67-kDa guanylate-binding protein (hGBP1) is a GTPase that converts GTP to GMP. 751 61

Tyrphostins are a group of organic compounds which are widely used as a tool to specifically inhibit protein tyrosine kinases (Yaish, P., Gazit, A., Gilon, C., and levitzki A. (1988) Science 242, 933-935; Gazit, A., Yaish, P., Gilon, C., and Levitzki A. (1989) J. Med. Chem. 32, 2344-2352; Lyall, R. M., Zilberstein, A., Gazit, A., Gilon, C., Levitzki, A., and Schlessinger J. (1989) J. Biol. Chem. 264, 14503-14509; Osherov, N., Gazit, A., Gilon, C., and Levitzki, A. (1993) J. Biol. Chem. 268, 11134-11142). We report here that members of the tyrphostin family inhibit the GTPase activity of transducin and the enzymatic activities of other GTP-utilizing proteins in retinal rod outer segments, such as guanylyl cyclase or fructose-6-phosphate kinase. In contrast, ATP-utilizing enzymes such as hexokinase or rhodopsin kinase were not effected.
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PMID:Inhibition of GTP-utilizing enzymes by tyrphostins. 791 15

We have recently found the calcium dependent glycogenolytic effect of a pancreastatin on rat hepatocytes and the mobilization of intracellular calcium. To further investigate the mechanism of action of pancreastatin on liver we have studied its effect on guanylate cyclase, adenylate cyclase, and phospholipase C, and we have explored the possible involvement of GTP binding proteins by measuring GTPase activity as well as the effect of pertussis toxin treatment of plasma liver membranes on the pancreastatin stimulated GTPase activity and the production of cyclic GMP and myo-inositol 1,4,5-triphosphate. Pancreastatin stimulated GTPase activity of rat liver membranes about 25% over basal. The concentration dependency curve showed that maximal stimulation was achieved at 10(-7)M pancreastatin (EC50 = 3 nM). This stimulation was partially inhibited by treatment of the membranes with pertussis toxin. The effect of pancreastatin on guanylate cyclase and phospholipase C were examined by measuring the production of cyclic GMP and myo-inositol 1,4,5-triphosphate respectively. Pancreastatin increased the basal activity of guanylate cyclase to a maximum of 2.5-fold the unstimulated activity at 30 degrees C, in a time- and dose-dependent manner, reaching the maximal stimulation above control with 10(-7) M pancreastatin at 10 min (EC50 = 0.6 nM). This effect was completely abolished when rat liver membranes had been ADP-ribosylated with pertussis toxin. On the other hand, adenylate cyclase activity was not affected by pancreastatin. Phospholipase C activity of rat liver membranes was rapidly stimulated (within 2-5 min) at 30 degrees C by 10(-7) M pancreastatin, reaching a maximum at 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pancreastatin activates pertussis toxin-sensitive guanylate cyclase and pertussis toxin-insensitive phospholipase C in rat liver membranes. 791 48


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