Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q07644 (polypeptide)
 72,197 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Crotoxin, the major toxin of the venom of the South American rattlesnake, Crotalus durissus terrificus, is made of two subunits: component B, a basic and weakly toxic phospholipase A2, and component A, an acidic and nontoxic protein that enhances the lethal potency of component B. Crotoxin is a mixture of isoforms that results from the association of several isoforms of its two subunits. In the present investigation, we have purified four component A isoforms that, when associated with the same purified component B isoform, produced different crotoxin isoforms, all having the same specific enzymatic activity and the same lethal potency. We further determined by Edman degradation the polypeptide sequences of these four component A isoforms. They are made of three disulfide-linked polypeptide chains (alpha, beta, and gamma) that correspond to three different regions of a phospholipase A2 precursor. We observed that the polypeptide sequences of the various component A isoforms all agree with the sequence of an unique precursor. The differences between the isoforms result first by differences in the length of the various chains alpha and beta, indicating that component A isoforms are generated from the proteolytic cleavage of the component A precursor at very close sites, possibly by the combined actions of endopeptidases and exopeptidases, and second by the possible cyclization of the alpha-NH2 of the N-terminal glutamine residue of chains beta and gamma. These observations indicate that the component A isoforms are the consequence of different posttranslational events occurring on an unique precursor, rather than the expression of different genes.
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PMID:Multiplicity of acidic subunit isoforms of crotoxin, the phospholipase A2 neurotoxin from Crotalus durissus terrificus venom, results from posttranslational modifications. 186 83

The GTPase activity of a G protein alpha subunit functions as a timer to control the lifetime of the activated conformation of the protein. Expression of the GTPase-deficient Gi2 alpha subunit oncogene, gip2 (alpha i2Q205L), in Chinese hamster ovary cells inhibited the stimulation of adenylylcyclase and altered the calcium regulation of the Gi2-phospholipase A2 (PLA2) effector complex. The phenotypic consequence of the activated alpha i2 mutant on hormonal stimulation of PLA2 varied depending on the cytoplasmic calcium transient elicited by different Gi2-linked receptors. The stimulation of PLA2 by thrombin, which mobilized calcium only from internal stores, was markedly attenuated in gip2-expressing cells. In contrast, the attenuation of the PLA2 response to ATP, a purinergic agonist which mobilizes calcium from both extracellular space and internal stores, was significantly less than that observed for thrombin. Ionomycin, a calcium ionophore, stimulated PLA2 activity in clones which expressed gip2 to a level similar to that observed in wild-type Chinese hamster ovary cells. Thus, the dominant GTPase-deficient gip2 polypeptide will constitutively inhibit adenylylcyclase but differentially modulate enzymes regulated by calcium and coupled to Gi2.
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PMID:GTPase-deficient G alpha i2 oncogene gip2 inhibits adenylylcyclase and attenuates receptor-stimulated phospholipase A2 activity. 190 71

1. Functional studies have been performed to evaluate the potential involvement of capsaicin-sensitive nerves in the bronchomotor responses evoked by lipid mediators produced from the metabolic breakdown of arachidonic acid (AA) in the guinea-pig bronchus. 2. In the presence of indomethacin, the exogenous administration of AA (0.01-1 mM) produced a concentration-dependent contractile response in guinea-pig isolated bronchial rings. AA-induced contractions were augmented by epithelium-removal and by thiorphan (10 microM), an inhibitor of tachykinin breakdown. A sustained downward and rightward displacement of the complete concentration-response curve to AA was observed after in vitro capsaicin desensitization. 3. BWA4C (1 microM), a selective inhibitor of 5-lipoxygenase, shifted the AA concentration-response curve to the right. In the presence of this inhibitor, capsaicin desensitization did not have any further inhibitory action. 4. A potent, concentration-dependent and capsaicin-sensitive bronchoconstrictor effect was also observed with the polypeptide, melittin (10 nM-1 microM), an activator of phospholipase A2, which therefore should generate endogenous AA. 5. In vitro capsaicin-desensitization produced a significant reduction of the bronchomotor responses evoked by lipoxin A4 (1-6 microM), but not of those elicited by other lipoxygenases products such as leukotriene D4 (1-100 nM) or by 15-hydroxyeicosatetraenoic acid (15-HETE, 1-6 microM). 6. These findings indicate that lipoxin A4 but not leukotriene D4 or 15-HETE, might be one of the lipoxygenase mediators of excitatory effects of AA on capsaicin-sensitive sensory nerves.
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PMID:Involvement of capsaicin-sensitive nerves in the bronchomotor effects of arachidonic acid and melittin: a possible role for lipoxin A4. 190 31

Human monoblast U937 cells contain a soluble phospholipase A2 (PLA2) that is activated over the range of 150-600 nM Ca2+ and is stable only at neutral pH. We have purified this PLA2 over 34,000-fold to near homogeneity using sequential ion exchange, hydrophobic interaction, and gel filtration chromatography steps. The protein has a Mr of approximately 100,000 (by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and an isoelectric point of 5.1. Four lines of evidence indicate that this 100-kDa polypeptide represents the PLA2. (i) The intensity of staining of the 100-kDa protein was proportional to the degree of purification of PLA2 activity, (ii) the relative staining intensity of the 100-kDa protein precisely paralleled the elution profile of PLA2 activity during chromatography steps, (iii) the PLA2 activity recovered from a nondenaturing gel (greater than 60% of the total activity applied) coincided exactly with the major high molecular weight protein detected by silver staining, and (iv) monoclonal antibodies against the 100-kDa protein immunoprecipitated the PLA2. We conclude that the cytosolic PLA2 isolated from U937 cells represents a novel, high molecular weight PLA2 responding to physiological (intracellular) changes in Ca2+ concentration and therefore may play a critical role in cellular signal transduction processes and the biosynthesis of lipid mediators.
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PMID:The Ca2(+)-sensitive cytosolic phospholipase A2 is a 100-kDa protein in human monoblast U937 cells. 200 59

We report the sequences of three cDNAs encoding the two subunits (CA and CB) of crotoxin, a neurotoxic phospholipase A2 from the venom of the South-American rattlesnake Crotalus durissus terrificus. CB is a basic and toxic phospholipase A2 and CA is an acidic, non toxic and non enzymatic three chain containing protein which enhances the lethal potency of CB. Two cDNAs encoding precursors of CB isoforms have been isolated from a cDNA library prepared from one venom gland. Both precursors are made of the same 16 residues signal peptide followed by a polypeptide of 122 amino acid residues. The two mature sequences differ from each other at eight positions and are in good agreement with the previous polypeptide sequence reported for CB. In the case of CA, the cDNA encodes a signal peptide identical to those found in CB precursors, followed by a polypeptide of 122 amino acids clearly homologous to phospholipases A2 and including three regions which correspond to the three chains of mature CA. This demonstrates that CA is generated from a phospholipase A2-like precursor, called pro-CA, by the removal of three peptides, leaving unchanged the molecule core cross-linked by disulfide bridges. The 5'-untranslated tracts of cDNAs encoding CA and CB are nearly identical and the 3'-untranslated tracts are very similar, suggesting that the mRNAs encoding the two crotoxin subunits may result from the alternative splicing of a single gene or from the existence of a recent gene conversion. Data have been analysed in light of recent results on other phospholipases A2 from different origins.
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PMID:Analysis of cDNAs encoding the two subunits of crotoxin, a phospholipase A2 neurotoxin from rattlesnake venom: the acidic non enzymatic subunit derives from a phospholipase A2-like precursor. 201 2

We describe a method to generate a novel representation for protein structures called "crepe ribbons." In our representation, each piece of the ribbon was constructed using the coordinates of the backbone atoms of each individual residue. Using the internal geometries of each residue and a helix-generating algorithm, a local origin and the direction cosines of a local orthogonal system were obtained. The locus of the local origins represents the folding of the polypeptide. A color-coded origin-origin distance plot similar to that of C alpha-C alpha distance plot was generated. This plot may be used to visually compare and contrast two structures. We identified linear regions in the distribution of the local origins and assigned a secondary structure description. Parameters describing the interrelation between various secondary structure segments were calculated. We have illustrated our crepe-ribbon representation by comparing two phospholipase A2 structures in the Brookhaven National Laboratory Protein Data Bank.
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PMID:Crepe-ribbon representation for protein structures: comparison of phospholipases A2. 201 54

Intact erythrocytes of different Rh genotypes were subjected to various enzyme treatments, the effects of which were monitored by separating the membrane proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and performing Western blotting using an antibody preparation that recognizes only Rh-related polypeptides. We found that treatment of intact cells with either phospholipase A2 or proteases such as papain did not alter the size of Rh antigen-containing polypeptides. In contrast, phospholipase A2 treatment followed by papain digestion cleaved a fraction of these polypeptides. This cleavage appears, from such digestions of Rh(D) positive and negative cells of different genotypes, to occur solely at the extracellular domain of Rh(D) polypeptide, while the extracellular domains of other Rh antigen-containing polypeptides are unaffected. Digestion of red blood cell ghosts and inside-out vesicles with trypsin showed that Rh(D), (C/c), and (E/e) antigen-containing polypeptides span the lipid bilayer having cytoplasmic domains susceptible to the action of proteases. The size of the cleavage products at the cytoplasmic domain of -D-/-D- cells was found to differ from that of other Rh(D) positive genotypes, due possibly to a difference in folding of Rh(D) polypeptide at its cytoplasmic domain and within the cellular membrane of these cells.
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PMID:Enzymatic evidence for differences in the placement of Rh antigens within the red cell membrane. 210 64

Rat kidney contains a soluble phospholipase A2 (PLA2), which is chromatographically identical with a previously identified hormonally regulated form of the enzyme in rat renal mesangial cells. This kidney enzyme has been purified by sequential column fractionation. The purified enzyme is a 110 kDa polypeptide which can hydrolyse arachidonoyl phosphatidylcholine and arachidonoyl phosphatidylethanolamine, but has low activity towards arachidonoyl phosphatidylinositol. The enzyme is considerably larger than most previously isolated forms of secretory or intracellular PLA2, and is stimulated by physiological concentrations of Ca2+, with half-maximal activation occurring at 500 nM-Ca2+. The hormonal regulation and Ca2(+)-dependency of this enzyme strongly suggest that it plays a role in hormonally regulated arachidonic acid release and prostaglandin production in the kidney.
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PMID:Purification of a high-molecular-mass form of phospholipase A2 from rat kidney activated at physiological calcium concentrations. 212 Nov 34

1. The present experiments were designed to determine the effect of melittin on renin secretion. Melittin is a polypeptide component of bee venom which stimulates phospholipase A2 activity, thereby increasing arachidonic acid release and prostaglandin (PG) synthesis, and which inhibits protein kinase C activity. Either of these actions might be expected to stimulate renin secretion, since renin secretion is stimulated by arachidonic acid and by several PGs, and since renin secretion is inhibited by several activators of protein kinase C. 2. In rat renin cortical slices incubated at 37 degrees C in a buffered and oxygenated physiological saline solution, 0.1-10 microM-melittin produced a concentration-dependent stimulation of both prostaglandin E2 (PGE2) synthesis and renin secretion. However, melittin-stimulated renin secretion is independent of melittin-stimulated phospholipase A2 activity, arachidonic acid release, and PG synthesis, since 20 microM-quinacrine (a phospholipase A2 antagonist) and 50 microM-meclofenamate (a cyclooxygenase antagonist) antagonized basal and melittin-stimulated PGE2 synthesis but had no effects on basal or melittin-stimulated renin secretion. 3. Furthermore, melittin-stimulated renin secretion is not produced by inhibition of protein kinase C, since an activator of protein kinase C (12-O-tetradecanoylphorbol 13-acetate, TPA), enhanced rather than antagonized melittin-stimulated renin secretion. Ouabain partially antagonized, but did not completely block, melittin-stimulated renin secretion. 4. Thus, melittin-stimulated phospholipase A2 activity probably accounts for stimulated PGE2 production, but not for stimulated renin secretion. The mechanism of melittin-stimulated renin secretion is unclear; an effect on protein kinase C does not appear to be involved, and in contrast to the stimulatory effects of a variety of other substances, melittin-stimulated renin secretion is only partially antagonized by ouabain.
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PMID:Effect of melittin on renin and prostaglandin E2 release from rat renal cortical slices. 223 11

A small polypeptide isolated from human serum inhibits the action of phospholipase A2 on dipalmitoylglycerol phosphocholine vesicles. Sequence analysis revealed the protein to be apolipoprotein C-1, a major component of very light-density lipoprotein. The inhibiting efficiency is increased by one order of magnitude after 10 min preincubation of the protein with the substrate, but not the enzyme. It also depends on the concentration of the phospholipid. IC50 is about 0.5 microM at 0.2 mM DPPC and 1 microM at 1 mM DPPC. Apolipoprotein C-1 is also inhibitory in a more physiological system: in broken human leukemia cells (HL-60 cells) it inhibits the release by endogenous phospholipases of arachidonic acid from membrane phospholipids. The effective concentrations correspond to those found in the serum. It is concluded that apolipoprotein C-1 and similar phospholipid-binding proteins may act as phospholipase inhibitors by blocking the access to the substrate.
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PMID:Apolipoprotein C-1 inhibits the hydrolysis by phospholipase A2 of phospholipids in liposomes and cell membranes. 230 19


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