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PubMed1975

Purification and properties of a yeast protein kinase.

A protein phosphokinase (EC 2.7.1.1.37) was isolated from baker's yeast (Saccharomyces cerevisiae) after a 17,000-fold purification; the purified enzyme is homogeneous according to the criteria of gel electrophoresis and ultracentrifuge analysis. The enzyme has a high isoelectric point of ca. 9 and appears to exist as a monomer with a molecular weight of 42,000 plus or minus 1500. It is neither stimulated by cyclic 3',5'-AMP, -GMP, -CMP or -ump nor inhibited by the regulatory subunit of rabbit muscle protein kinase (Reimann, E. M., Walsh, D. A., and Krebs, E. G. (1971), J. Biol. Chem. 246, 1986). In the presence of divalent metal ions, preferably Mg-2+ or Mn-2+, the enzyme readily transfers the terminal phosphate group of ATP to phosvitin, alphaS1B- and beta a-casein and an NH2-terminal tryptic peptide derived from beta a-casein, but not to protamine, lysine, or arginine-rich histones or to yeast enzymes such as phosphorylase, phosphofructokinase, or pyruvate carboxylase; serine and polyserine were also inactive as phosphate acceptors. Km values of 0.17 mM for beta a-casein and 0.2 mMfor ATP were determined at 10 mM Mg-2+. The urified yeast protein kinase also catalyzes the reverse reaction, namely, the transfer of phosphate from fully phosphorylated beta a-casein or its NH2-terminal peptide to ADP resulting in the formation of ATP. AMP, GDP, UDP, and CDP did not serve as phosphate acceptors in this reaction. As observed by Rabinowitz and Lipmann (Rabinowitz, M., and Lipmann, F. (1960), J. Biol. Chem. 235, 1043) both reactions have different pHoptima with values of 7.5 for the forward reaction (phosphorylation of the proteins) and ca 5.2 for the formation of ATP; both are differently affected by salts. Phosphorylation of beta a-casein with [gamma-32-P]ATP followed by digestion of the labeled protein with trypsin indicated that all the radioactivity was exclusively introduced in an NH2-terminal peptide possessing the unique sequence: Glu-Ser(P)-Leu-Ser(P)-Ser(P)-Ser(P)-Glu-Glu...(Ribadeau-Dumas, B., Brignon, G., Grosclaude, F., and Mercier, J.-C. (1971), eur J. Biochem. 20, 264). By subjecting beta a-casein and its NH2-terminal peptide to the combined action of almond acid phosphatease and purified yeast protein kinase, it was determined that the phosphorylation and dephosphorylation reactions proceed randomly, i.e., all seryl phosphate residues are equally susceptible and that the rate of phosphorylation decreases drastically as the number of bound phosphate groups in the substrate diminishes.

Amino Acids↗
PubMed1971

Inhibition of replication in functional mouse adrenal tumor cells by adrenocorticotropic hormone mediated by adenosine 3':5'-cyclic monophosphate.

Adrenocorticotropic hormone (ACTH) inhibited replication in functional adrenal tumor cells with a concomitant stimulation of steroidogenesis and a characteristic change of morphology from a flattened to a spherical type. [(3)H]Thymidine incorporation into DNA was inhibited by about 50% 6 hours after ACTH treatment. Both cyclic AMP and dibutyryl cyclic AMP inhibited [(3)H]thymidine incorporation and caused the characteristic morphological change noted with ACTH. The extent of stimulation of steroidogenesis and the amount of inhibition of [(3)H]thymidine incorporation in response to various doses of ACTH were closely related and both were in parallel with the concentration of cyclic AMP in the cells. Cyclic GMP and cyclic IMP did not inhibit [(3)H]thymidine incorporation significantly, and did not change the morphology of the cells. AMP inhibited [(3)H]thymidine incorporation into DNA and caused the characteristic morphological change. However, AMP did not increase the cyclic AMP content of the cells. CMP, GMP, and UMP showed a significant inhibition of [(3)H]thymidine incorporation into DNA, but the extent of the inhibition was much less than that with AMP. These nucleotides did not change the morphology of the cells.

Adrenal Gland Neoplasms↗
PubMed1998

The subsites structure of bovine pancreatic ribonuclease A accounts for the abnormal kinetic behavior with cytidine 2',3'-cyclic phosphate.

The kinetics of the hydrolysis of cytidine 2',3'-cyclic phosphate (C>p) to 3'-CMP by ribonuclease A are multiphasic at high substrate concentrations. We have investigated these kinetics by determining 3'-CMP formation both spectrophotometrically and by a highly specific and quantitative chemical sampling method. With the use of RNase A derivatives that lack a functional p2 binding subsite, evidence is presented that the abnormal kinetics with the native enzyme are caused by the sequential binding of the substrate to the several subsites that make up the active site of ribonuclease. The evidence is based on the following points. 1) Some of the unusual features found with native RNase A and C>p as substrate disappear when the derivatives lacking a functional p2 binding subsite are used. 2) The kcat/Km values with oligocytidylic acids of increasing lengths (ending in C>p) show a behavior that parallels the specific velocity with C>p at high concentrations: increase in going from the monomer to the trimer, a decrease from tetramer to hexamer, and then an increase in going to poly(C). 3) Adenosine increases the kcat obtained with a fixed concentration of C>p as substrate. 4) High concentrations of C>p protect the enzyme from digestion with subtilisin, which results in a more compact molecule, implying large substrate concentration-induced conformational changes. The data for the hydrolysis of C>p by RNase A can be fitted to a fifth order polynomial that has been derived from a kinetic scheme based on the sequential binding of several monomeric substrate molecules.

Adenosine↗
PubMed1992

Lithium treatment of affective disorders: effects of lithium on the inositol phospholipid and cyclic AMP signalling pathways.

The effects of lithium (Li+) on the adenylyl cyclase and inositol phospholipid receptor signalling pathways were compared directly in noradrenergic and carbachol stimulated rat brain cortical tissue slices. Li+ was a comparatively weak inhibitor of noradrenaline-stimulated cyclic AMP accumulation with an IC50 of approx. 20 mM. By contrast, half-maximal effects of Li+ on inositol monophosphate (InsP) accumulation in [3H]inositol labelled tissue slices occurred at about 1 mM. A similar IC50 for Li+ of about 1 mM was also obtained for noradrenaline-stimulated accumulation of CMP-phosphatidate (CMPPA), a sensitive indicator of intracellular inositol depletion, in tissue slices that had been prelabelled with [3H]cytidine. The effect of myo-inositol (inositol) depletion on the prolonged activity of phosphoinositidase C (PIC) was examined in carbachol-stimulated cortical slices using a novel mass assay for InsP. Exposure to a maximal dose of carbachol for 30 min in the presence of 5 mM Li+ caused a 10-fold increase in the level of radioactivity associated with the InsP fraction, but only a 2-fold increase in InsP mass. During prolonged incubations in the presence of both carbachol and Li+ the accumulation of InsP mass was enhanced if 30 mM inositol was included in the medium. The results are compatible with the inositol depletion hypothesis of Li+ action but do not support the concept that adenylyl cyclase or guanine nucleotide dependent proteins represent therapeutically relevant targets of this drug.

Animals↗
PubMedDate not supplied

[Premature termination--a multifactoral phenomenon].

Twelve drop out cases in psychodynamic short term therapies according to the focus of cyclic maladaptive pattern by Strupp and Binder (CMP 1984) are reviewed regarding initial diagnostics, tape-recorded therapy sessions, and supervision records. Predictors of premature termination of therapy such as initially rated patients' therapy motivation, narcissistic personality traits, but also characteristics of interpersonal behavior of both patient and therapist are examined and discussed. Particularly important are the therapeutic alliance and narcissistic patients' difficulties to relate personally to their therapists instead of enacting projective dynamics of idealization and devaluation. Therapists frequently tend to respond to them by subconscious display of hostile countertransference. Four patterns of dynamics of therapy drop outs are described.

Adult↗
PubMed2002

Continuous low dose of melphalan and prednisone in patients with multiple myeloma of very old age or severe associated disease.

INTRODUCTION AND OBJECTIVE: The management of elderly patients with multiple myeloma is a relevant problem because it concerns a great number of patients. Patients with multiple myeloma who are very old or who have severe associated diseases have a dismal outcome. For these patients we retrospectively evaluated the effect of a mild approach with continuous low-dose melphalan and prednisone (cMP). DESIGN AND METHODS: 109 patients with multiple myeloma, observed between 1985 and 2000, were treated with cMP; 67 were treated at time of diagnosis (group A; median age 78 years) and 42 as a second or subsequent line of therapy (group B; median age 72 years). The toxicity of the treatment was compared with a control group of 29 patients aged over 70 years, treated in the same institution with the conventional cyclical melphalan/prednisone regimen. RESULTS: Major or minor responses were obtained in 32% of patients in group A and 13% of patients in group B. Disease was stabilised in 45% of group A and 47% of group B and progressed in 5 and 18%, respectively. Median survival was, respectively, 19 and 24 months in group A and B. Among the 42 patients who received cMP as a second-line therapy (group B), 36 (86%) had previously been treated according to the standard cyclical melphalan/prednisone schedule; of these 12 (33%) obtained a better M protein reduction after cMP compared with the previous response to first-line cyclical melphalan/prednisone. The cMP schedule was generally well tolerated, and the rate of haematological toxicity was lower than for a historical control group receiving cyclical melphalan/prednisone. CONCLUSION: The cMP treatment schedule is well tolerated and results in a high proportion of patients with stable disease, with acceptable survival even in patients with advanced disease.

Aged↗
PubMed1994

Structure and conformation of the cyclic phosphate of Ganciclovir, a broad-spectrum antiviral agent.

The title compound, the cyclic phosphate of the antiviral acyclonucleoside Ganciclovir (2'-NDG, DHPG), is itself a potent broad-spectrum antiviral agent, but with a different mechanism of action. The cyclic phosphate, 9-[[[(2-hydroxy-1,3,2-dioxophosphorinan-5-yl)oxy]methyl]-P- oxide]guanine (2'-nor-cGMP,DHPG-cMP), crystallizes in the monoclinic space group P2(1)/n with unit cell dimensions a = 6.612(1) A, b = 11.562(4) A, c = 19.231(5) A and beta = 91.786(2) degrees at -165 degrees C. The N7 of the guanine base is protonated, so that the molecule is in a zwitterionic form, with two water molecules in the asymmetric unit. The principal conformational features of DHPG-cMP in the crystal are as follows: the acyclic chain is partially folded; the six-membered cyclic phosphate ring is in a chair form with C3', O3', C5' and O5' in a plane; P and C4' are displaced in diametrically opposite directions from this plane; the O4' is in the axial orientation with respect to this ring; and the aglycon is in the high syn conformation about the glycosidic bond. The conformation of the cyclic phosphate ring in aqueous medium, determined by means of 1H-NMR spectroscopy, is similar to that in the crystalline form. The conformational features of DHPG-cMP were compared with those of the parent DHPG and other related compounds and, in particular, with those of the second messenger 3':5'-cGMP, of which it is a close structural analogue. Previously reported substrate/inhibitor properties of these compounds in several enzyme systems are examined in relation to the possible mechanism of antiviral activity of DHPG-cMP as a second messenger analogue of cGMP.

Antiviral Agents↗
PubMed1987

The analysis of enzyme progress curves by numerical differentiation, including competitive product inhibition and enzyme reactivation.

A new method for analyzing steady-state enzyme kinetic data is presented. The technique, which is based on the numerical differentiation of the complete reaction curve, has several advantages over initial velocity and integrated Michaelis-Menten equation methods. The differentiated data are fit to the differential equation describing the appropriate kinetic scheme. This approach is particularly valuable in cases of strong competitive product inhibition and of changing concentrations of active enzyme. The method assumes a reversible reaction and is applicable to a very wide variety of steady-state kinetic schemes. A particular advantage of this approach over integrated methods is that it is independent of [S0] and hence of errors in [S0]. The combination of complete progress curve and computer analysis makes this approach very efficient with respect to both time and materials. Running on an IBM PC XT or equivalent microcomputer with an 8087 coprocessor, the analyses are very fast, the complete process usually being complete in a minute or two. The utility of the technique is demonstrated by application to both simulated and real data. We show that the differentiation of the progress curve for the ribonuclease-catalyzed hydrolysis of 2',3'-cyclic cytidine monophosphate reveals strong product inhibition by 3'-CMP, and this product inhibition accounts for the large discrepancies reported in the literature for the value of Km for this substrate. The method was also applied to determine the rate of reactivation of beta-lactamase which had been reversibly inactivated by cloxacillin. Since large numbers of data points are required for the numerical differentiation the method has become practical only with the advent of computer-acquired data systems.

Bacillus cereus↗
PubMed1977

Formation of ribonucleotide 2',3'-cyclic carbonates during conversion of ribonucleoside 5'-phosphates to diphosphates and triphosphates by the phosphorimidazolidate procedure.

Ribo- and 2'-deoxyribonucleoside 5'-di- or triphosphates are commonly synthesized by reaction of inorganic phosphate or pyrophosphate with phosphorimidazolidates obtained by reaction of nucleoside 5'-phosphates with 1,1'-carbonyldiimidazole. The latter reaction, however, converted UMP, CMP, IMP, GMP, and AMP in high yield to the 2',3'-cyclic carbonate derivatives of their phosphorimidazolidates. Acidic treatment of the product from AMP gave AMP 2',3'-cyclic carbonate dihydrate; this was characterized by its uv, ir, and pmr spectra and by its conversion to adenosine 2',3'-cyclic carbonate by acid phosphatase and to AMP by basic hydrolysis. ADP or ATP synthesized by the phosphorimidazolidate method contained equal or greater amounts of their respective 2',3'-cyclic carbonates. The latter could be quantitatively converted to ADP and ATP, respectively, by 4-hr hydrolysis at pH 10.5, 22 degrees. ADP or ATP can be synthesized without concomitant 2',3'-cyclic carbonate formation by reaction of AMP with phosphorimidazolidates of inorganic phosphate or pyrophosphate.

Carbonates↗
PubMed1983

Repressible extracellular phosphodiesterases showing cyclic 2',3'- and cyclic 3',5'-nucleotide phosphodiesterase activities in Neurospora crassa.

Two molecular species of repressible extracellular phosphodiesterases showing cyclic 2',3'- and cyclic 3',5'-nucleotide phosphodiesterase activities were detected in mycelial culture media of wild-type Neurospora crassa and purified. The two molecular species were found to be monomeric and polymeric forms of an enzyme constituted of identical subunits having molecular weights of 50,000. This enzyme had the same electrophoretic mobility as repressible acid phosphatase. The enzyme designated repressible cyclic phosphodiesterase showed pH optima of 3.2 to 4.0 with a cyclic 3',5'-AMP substrate and 5.0 to 5.6 with a cyclic 2',3'-AMP substrate. Repressible cyclic phosphodiesterase was activated by MnCl2 and CoCl2 with cyclic 2',3'-AMP as substrate and was slightly activated by MnCl2 with cyclic 3',5'-AMP. The enzyme hydrolyzed cyclic 3',5'- and cyclic 2',3'-nucleotides, in addition to bis-rho-nitrophenyl phosphate, but not certain 5' -and 3'-nucleotides. 3'-GMP and 3'-CMP were hydrolyzed less efficiently. Mutant strains A1 (nuc-1) and B1 (nuc-2), which cannot utilize RNA or DNA as a sole source of phosphorus, were unable to produce repressible cyclic phosphodiesterase. The wild type (74A) and a heterocaryon between strains A1 and B1 produced the enzyme and showed growth on orthophosphate-free media containing cyclic 2',3'-AMP or cyclic 3',5'-AMP, whereas both mutants showed little or no growth on these media.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1989

Multinuclear NMR study of the interaction of vanadate with mononucleotides, ADP, and ATP.

The interaction of vanadate with 5'-mononucleotides, ADP, ATP, and various molecules containing some of their chemical moieties was studied in aqueous solution in the pH region of 5-9 using proton, 13C, 31P, and 51V nuclear magnetic resonance (NMR) spectroscopy. All the compounds studied formed noncyclic vanadate esters through interaction of monovanadate or divanadate with the hydroxyl groups of the ribose ring. Noncyclic anhydrides were also formed with the phosphate groups of ribose 5-phosphate, the mononucleotides, ADP, ATP, phosphate, pyrophosphate, and tripolyphosphate. In particular, ADP and ATP analogs resulted from AMP (AMPV and AMPV2) and from ADP (ADPV). Cyclic esters of trigonal bipyramidal geometry resulted from the interaction of vanadate with two ribose ring cis hydroxyl groups. AMP, CMP, and UMP formed two such complexes of 1:1 and 1:2 stoichiometries, similar to what has been observed for uridine and other nucleosides. However, 2'-deoxy-AMP does not yield this type of complexes. ADP and ATP also form similar cyclic ester complexes with vanadate, which does not chelate their pyrophosphate and tripolyphosphate moieties. Nevertheless, the separate pyrophosphate (PP) and tripolyphosphate (PPP) ligands form cyclic anhydrides of octahedral geometry with vanadate. However, their binding to vanadate is weaker than that of the ribose ring of nucleotides. Competition experiments between ethylene glycol and phosphate (P), pyrophosphate (PP), or tripolyphosphate (PPP) show that the relative strength of the interaction of these ligands with vanadate is PP greater than ethylene glycol greater than PPP greater than P.

Adenosine Diphosphate↗
PubMed2003

Highly selective binding of organometallic ruthenium ethylenediamine complexes to nucleic acids: novel recognition mechanisms.

We have investigated the recognition of nucleic acid derivatives by organometallic ruthenium(II) arene anticancer complexes of the type [(eta(6)-arene)Ru(II)(en)X] where en = ethylenediamine, arene = biphenyl (Bip), tetrahydroanthracene (THA), dihydroanthracene (DHA), p-cymene (Cym) or benzene (Ben), X = Cl(-) or H(2)O using (1)H, (31)P and (15)N ((15)N-en) NMR spectroscopy. For mononucleosides, [(eta(6)-Bip)Ru(en)](2+) binds only to N7 of guanosine, to N7 and N1 of inosine, and to N3 of thymidine. Binding to N3 of cytidine was weak, and almost no binding to adenosine was observed. The reactivity of the various binding sites of nucleobases toward Ru at neutral pH decreased in the order G(N7) > I(N7) > I(N1), T(N3) > C(N3) > A(N7), A(N1). Therefore, pseudo-octahedral diamino Ru(II) arene complexes are much more highly discriminatory between G and A bases than square-planar Pt(II) complexes. Such site-selectivity appears to be controlled by the en NH(2) groups, which H-bond with exocyclic oxygens but are nonbonding and repulsive toward exocyclic amino groups of the nucleobases. For reactions with mononucleotides, the same pattern of site selectivity was observed, but, in addition, significant amounts of the 5'-phosphate-bound species (40-60%) were present at equilibrium for 5'-TMP, 5'-CMP and 5'-AMP. In contrast, no binding to the phosphodiester groups of 3', 5'-cyclic-GMP (cGMP) or cAMP was detected. Reactions with nucleotides proceeded via aquation of [(eta(6)-arene)Ru(en)Cl](+), followed by rapid binding to the 5'-phosphate, and then rearrangement to give N7, N1, or N3-bound products. Small amounts of the dinuclear species, e.g., Ru-O(PO(3))GMPN7-Ru, Ru-O(PO(3))IMPN1-Ru, Ru-O(PO(3))TMPN3-Ru, Ru-N7IMPN1-Ru, and Ru-N7InoN1-Ru were also detected. In competitive binding experiments for [(eta(6)-Bip)Ru(en)Cl](+) with 5'-GMP versus 5'-AMP or 5'-CMP or 5'-TMP, the only final adduct was [(eta(6)-Bip)Ru(en)(N7-GMP)]. Ru-H(2)O species were more reactive than Ru-OH species. The presence of Cl(-) or phosphate in neutral solution significantly decreased the rates of Ru-N7 binding through competitive coordination to Ru. In kinetic studies (pH 7.0, 298 K, 100 mM NaClO(4)), the rates of reaction of cGMP with [(eta(6)-arene)Ru(II)(en)X](n+) (X = Cl(-) or H(2)O) decreased in the order: THA > Bip > DHA >> Cym > Ben, suggesting that N7-binding is promoted by favorable arene-purine hydrophobic interactions in the associative transition state. These findings have revealed that the diamine NH(2) groups, the hydrophobic arene, and the chloride leaving group have important roles in the novel mechanism of recognition of nucleic acids by Ru arene complexes, and will aid the design of more effective anticancer complexes, as well as new site-specific DNA reagents.

Adenosine↗
PubMed1990

Oligomerization reactions of deoxyribonucleotides on montmorillonite clay: the effect of mononucleotide structure, phosphate activation and montmorillonite composition on phosphodiester bond formation.

2'-d-5'-GMP and 2'-d-5'-AMP bind 2 times more strongly to montmorillonite 22A than do 2'-d-5'-CMP and 5'-TMP. The dinucleotide d(pG)2 forms in 9.2% yield and the cyclic dinucleotide c(dpG)2 in 5.4% yield in the reaction of 2'-d-5'-GMP with EDAC in the presence of montmorillonite 22A. The yield of d(pC)2 (2.0%) is significantly lower but comparable to that obtained from 5'-TMP. The yield of dimers which contain the phosphodiester bond decreases as the reaction medium is changed from 0.2 M NaCl to a mixture of 0.2 M NaCl and 0.075 M MgCl2. A low yield of d(pA)2 was observed in the condensation reaction of 5'-ImdpA on montmorillonite 22A. The cyclic nucleotide (3',5'-cdAMP) was obtained in 14% yield from 3'-ImdpA. The yield of d(pA)2 obtained when EDAC is used as the condensing agent increases with increasing iron content of the Na(+)-montmorillonite used as a catalyst. Evidence is presented which shows that the acidity of the Na(+)-montmorillonite is a necessary but not sufficient factor for the montmorillonite catalysis of phosphodiester bond formation.

Bentonite↗
PubMed2000

Mechanoregulation of chondrocyte proliferation, maturation, and hypertrophy: ion-channel dependent transduction of matrix deformation signals.

Mechanical stress-induced matrix deformation plays a fundamental role in regulating cellular activities; however, little is known about its underlying mechanisms. To understand the effects of matrix deformation on chondrocytes, we characterized primary chondrocytes cultured on three-dimensional collagen scaffoldings, which can be loaded mechanically with a computer-controlled "Bio-Stretch" device. Cyclic matrix deformation greatly stimulated proliferation of immature chondrocytes, but not that of hypertrophic chondrocytes. This indicates that mechanical stimulation of chondrocyte proliferation is developmental stage specific. Synthesis of cartilage matrix protein (CMP/matrilin-1), a mature chondrocyte marker, and type X collagen, a hypertrophic chondrocyte marker, was up-regulated by stretch-induced matrix deformation. Therefore, genes of CMP and type X collagen are responsive to mechanical stress. Mechanical stimulation of the mRNA levels of CMP and type X collagen occurred exactly at the same time points when these markers were synthesized by nonloading cells. This indicates that cyclic matrix deformation does not alter the speed of differentiation, but affects the extent of differentiation. The addition of the stretch-activated channel blocker gadolinium during loading abolished mechanical stimulation of chondrocyte proliferation, but did not affect the up-regulation of CMP mRNA by mechanical stretch. In contrast, the calcium channel blocker nifedipine inhibited both the stretch-induced proliferation and the increase of CMP mRNA. This suggests that stretch-induced matrix deformation regulates chondrocyte proliferation and differentiation via two signal transduction pathways, with stretch-activated channels involved in transducing the proliferative signals and calcium channels involved in transducing the signals for both proliferation and differentiation.

Animals↗
PubMed1989

Effects of adenine nucleotides on choriogonadotropin alpha and beta subunit synthesis.

The alpha subunit of human chorionic gonadotropin (CG) contains a discrete cAMP response element in the 5' flanking region of the gene. Since cAMP also stimulates the synthesis of the CG beta subunit the presence of a cAMP cis element in the CG beta gene was examined. Deletion mutants bearing various lengths of CG beta 5' region in front of the chloramphenicol acetyl transferase (CAT) gene were transfected in placental tumor cells. No discrete cAMP response element could be identified. Unexpectedly we also observed that AMP and adenosine not only stimulated CAT activity driven by CG beta promoter sequences but also enhanced synthesis of CG alpha and beta subunits in cultured choriocarcinoma cells. GMP, CMP, guanosine, and cytosine were inactive at comparable concentrations. These data suggest that the response of the CG alpha and beta genes to the non-cyclic adenine derivatives occurs by a mechanism that differs from cAMP.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Regulation of phospholipase C-beta 4 by ribonucleotides and the alpha subunit of Gq.

The fourth member of mammalian beta-type phospholipase C isozymes, PLC-beta 4, was recently purified from bovine retina, and the corresponding cDNA was cloned from rat brain and sequenced. PLC-beta 4 has now been shown to differ from the other three mammalian beta-type isozymes (PLC-beta 1, -beta 2, and -beta 3) in that it is selectively inhibited by ribonucleotides. The inhibition requires the 5'-phosphate and 2'-hydroxyl groups of ribose as well as the base moiety. Thus, deoxyribonucleotides and ribose 5-phosphate were not inhibitory. The monophosphate, diphosphate, and triphosphate nucleoside derivatives were all inhibitory, whereas cyclic nucleotides were ineffective. Purine nucleotides were more potent inhibitors than pyrimidine nucleotides; the 50% inhibitory concentrations were 20-30 microM for AMP and GMP, and 100-200 microM for UMP and CMP. Unlike the other beta-type isozymes, PLC-beta 4 contains the GX4GKS consensus sequence for the recognition of the phosphoryl group of nucleotides. In the absence of ribonucleotides, the specific activity of PLC-beta 4 toward phosphatidyl-inositol 4,5-bisphosphate was four to five times the average specific activity of PLC-beta 1 and PLC-beta 3. Thus, nucleotide-dependent inhibition may serve to reduce the activity of PLC-beta 4 in the absence of a hormonal signal. The regulation of PLC-beta 4 by G-proteins was also studied. Similar to the other three PLC-beta isozymes, PLC-beta 4 was activated by the alpha subunit of Gq but not by the transducin alpha subunit. However, unlike other PLC-beta isozymes, PLC-beta 4 was not responsive to activation by G beta gamma subunits.

Amino Acid Sequence↗
PubMed1977

Nucleotide-induced inhibition of surface sialyl transferase activity on cultured Burkitt's lymphoma cells.

Sialyl transferase activity was demonstrated on the surfaces of intact, cultured lymphoblastoid cells (RAJI) derived from a Burkitt's lymphoma. Pretreatment of the cells with neuraminidase increased the labeled sialoprotein by severalfold. A nunber of nucleotides were effective in decreasing the amount of sialoprotein assembly. CMP was the most effective inhibitor. UMP, AMP, and GMP were also inhibitory, but to a lesser degree. The diphosphate derivatives were similarly inhibitory, but generally less active than their monophosphate counterparts. The cyclic nucleotides were the least effective of all nucleotides tested; cCMP and cAMP showed a small degree of activity, whereas cUMP and cGMP were without effect. These studies indicated that a number of noncyclic and cyclic nucleotides can influence the activity of the sialyl transferase system.

Adenosine Monophosphate↗