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)

A toxic component (AgTx) from the venom of Agkistrodon halys (Pallas) was isolated using DEAE-cellulose DE11 and CM-Sephadex C50 column chromatography and finally purified to homogeneity by FPLC on a MonoQ column. The toxin is a neutral (pI 6.9) single chain polypeptide with a mol. wt of 14,000 and an amino acid composition (123 residues) roughly similar to that of notexin. AgTx was found to have phospholipase A2 activity which was dependent on calcium and stimulated by sodium deoxycholate. The toxin caused efflux of 2-deoxy-(1-3H)-glucose-6-phosphate (a cell membrane integrity probe) as well as of [3H]acetylcholine from rat brain synaptosomes. No cell membrane damage was induced by AgTx on cultured N1E 115 neuroblastoma cells and chick myotube cultures. The LD50 ws 150 micrograms/kg (i.p.) in mice. The main symptom observed was respiratory paralysis. The results obtained show that AgTx can be classified as a toxic phospholipase A2 with a presynaptic site of action.
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PMID:Some biochemical characteristics and cell membrane actions of a toxic phospholipase A2 isolated from the venom of the pit viper Agkistrodon halys (Pallas). 367 47

Vascular relaxation in response to acetylcholine and other vasodilator compounds has been shown to depend on intact endothelial cells. These dilator compounds obviously induce the formation of an unstable endothelium-derived relaxing factor or factors (EDRF) from the intima which relax the subjacent smooth muscle cells. The chemical identity of this factor (these factors) is still unclear. In the present study we demonstrate that endothelium-dependent relaxation of rabbit aorta was induced by melittin, a polypeptide toxin that activates phospholipase A2 to liberate polyunsaturated fatty acids (especially arachidonic acid) from membrane phospholipids. The relaxation induced by melittin had several properties similar to the acetylcholine relaxation. It was inhibited by potential inhibitors of phospholipase (mepacrine and p-bromophenacylbromide), by inhibitors of lipoxygenase (nordi-hydroguaiaretic acid, compound BW 755C, and 5,8,11,14-eicosatetraynoic acid) but not by the cyclooxygenase inhibitor indomethacin. An exogenous preparation of phospholipase C also induced endothelium-dependent relaxations. These findings support the hypothesis that oxidized metabolites of polyunsaturated fatty acids (e.g., arachidonic acid) may be involved directly (as mediators) or indirectly in the process of endothelium-dependent relaxation. On the other hand, exogenous arachidonic acid was a comparatively weak endothelium-dependent relaxant. However, this does not exclude an important role of endogenous arachidonic acid since the exogenous acid may not sufficiently reach its site of metabolism.
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PMID:Endothelium-dependent vasodilation by melittin: are lipoxygenase products involved? 392 96

Antisera were raised against the presynaptic neurotoxin beta-bungarotoxin and against its phospholipase-inactive derivative, modified by reaction with p-bromophenacyl bromide. The cross-reactivity of the antisera to other phospholipase A2 enzymes and polypeptide neurotoxins was examined. The antisera inhibited both the neurotoxic effects of beta-bungarotoxin at the frog motor endplate and the enzymatic activity of the toxin on model phospholipid membranes, although it is unlikely that the catalytic active centre is the locus of any major determinant.
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PMID:Antibodies to beta-bungarotoxin and its phospholipase inactive derivative. 618 70

We have purified a small, basic protein with high affinity and selectivity for biogenic amine receptors to apparent homogeneity from the venom of Russell's viper (Vipera russelli). This protein, which we designate "vipoxin," has Mr = 13,000, and appears to exist in solution as a single polypeptide chain. It may contain 2 atypical amino acids. Vipoxin inhibits in a dose-dependent manner the binding of 3H-ligands to biogenic amine receptors, with apparent Ki values of 3 nM at alpha 1-adrenergic receptors, 5 nM at alpha 2-adrenergic receptors, 15 nM at dopamine receptors, and 32 nM at serotonin receptors. At concentrations up to 1 microM, vipoxin is inactive at beta-adrenergic, histamine, nicotinic cholinergic, muscarinic cholinergic, adenosine, gamma-aminobutyric acid, benzodiazepine, or opiate receptor binding sites. The effect of vipoxin is essentially irreversible over 20 h at alpha 1- and alpha 2-adrenergic receptors and serotonin receptors and is only slightly reversible at dopamine receptors. Norepinephrine protects alpha-adrenergic receptors from inhibition by vipoxin, while dopamine does not. Vipoxin has no protease activity but does have phospholipase A2 activity, which cannot account for its action on receptors, since receptor binding is assayed in the presence of 1 mM CoSO4 which completely and selectively inhibits the phospholipase activity. Other phospholipases A2 in the same venom lack vipoxin's action on receptors. In physiologic experiments, vipoxin behaves as an agonist at alpha 2-adrenergic receptors in the rat vas deferens and is over an order of magnitude more potent than norepinephrine itself. At alpha 1-adrenergic receptors, it is neither a simple agonist nor an antagonist, but selectively potentiates norepinephrine. Vipoxin may be a useful tool for biogenic amine receptor characterization.
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PMID:Vipoxin. A protein from Russell's viper venom with high affinity for biogenic amine receptors. 627 17

A single chain polypeptide, termed beta-RTX, with an apparent Mr = 9600 has been isolated from the venom of Vipera russelli russelli. It was purified by cation exchange chromatography, followed by preparative isoelectric focusing and chromatofocusing. Purity was confirmed by gel filtration, high performance liquid chromatography, gel electrophoresis, and analytical ultracentrifugation. Amino acid analysis revealed the presence of eight half-cystines, one being located at the NH2 terminus, which are linked to form four intramolecular disulfide bridges. Chromatofocusing revealed some microheterogeneity yielding three isoforms with pI values of 9.3, 9.37, and 9.48, respectively. In its native configuration, beta-RTX was not susceptible to tryptic degradation but was readily digested after reduction and alkylation. beta-RTX possesses weak phospholipase A2 activity and competes with the binding of monoamines and opiate ligands to their respective receptors. No binding to histamine, gamma-aminobutyric acid, benzodiazepine, or muscarinic receptors was observed. In vivo, whereas 100 micrograms/kg intravenous beta-RTX seemed to be without apparent effects in the rat, 10 ng/kg beta-RTX injected intracerebroventricularly caused marked sedation, with full recovery within 3 h.
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PMID:beta-RTX. A receptor-active protein from Russell's viper (Vipera russelli russelli) venom. 630 Jan 28

The complete amino acid sequence of phospholipase A2 (phosphatide 2-acylhydrolase, EC 3.1.1.4) from human pancreas was determined. The protein consists of a single polypeptide chain of 125 amino acids and has a molecular weight of 14003. The chain is cross-linked by seven disulfide bridges. The main fragmentation of the polypeptide chain was accomplished by digestion of the reduced and thialaminated derivative of the protein with clostripain, yielding three fragments. The largest fragment (residues 7-100) was further degraded both with staphylococcal proteinase and chymotrypsin. The sequence was determined by automated Edman degradation of the intact protein and of several large peptide fragments. Phospholipase A2 from human pancreas contains the same number of amino acids (125) as the enzyme from horse, while the enzymes from pig and ox contain 124 and 123 residues, respectively. The enzymes show a high degree of homology; human phospholipase differs from the other enzymes by substitutions of 26 (porcine), 28 (bovine) and 32 (equine) residues, respectively.
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PMID:The complete primary structure of phospholipase A2 from human pancreas. 634 96

Melittin, a 26-amino acid polypeptide contained in bee venom and an activator of phospholipase A2, stimulated PRL secretion from bovine anterior pituitary cells in vitro. Over the dose range 0.25-2 micrograms/ml, melittin stimulation of PRL release was dose-related, reversible, and calcium dependent. Within this same dose range melittin did not deplete cell PRL stores, nor did it alter [3H]leucine uptake or trypan blue exclusion, indicators of cell viability. The phospholipase A2 inhibitors quinacrine and dibromoacetophenone blocked stimulation of PRL release by melittin and by themselves inhibited spontaneous PRL secretion. Addition of phospholipase A2 to pituitary cell cultures was associated with increased PRL secretion. A possible product of phospholipase A2 action, arachidonic acid, also stimulated PRL release. Indomethacin, an inhibitor of arachidonic acid conversion to prostaglandins, did not block melittin-induced PRL release but instead enhanced it. These data suggest that phospholipase A2 may participate in controlling PRL secretion by causing release of arachidonic acid from membrane phospholipids. Arachidonic acid or its noncyclooxygenase metabolite may serve as an intracellular regulator of secretion in the lactotroph.
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PMID:Stimulation of anterior pituitary prolactin release by melittin, an activator of phospholipase A2. 641 21

In phospholipase A2 from Naja melanoleuca snake venom all four lysines were converted into the epsilon-amidinated derivatives without reaction of the alpha-amino group. The amidinated phospholipase (AMPA) showed high enzymatic activity. Starting from AMPA, chemical modification reactions were carried out at the alpha-amino function. This group was blocked with a tert-butyloxycarbonyl or a phenylthiocarbamyl group. Furthermore the polypeptide chain was shortened by one residue by removing the N-terminal asparagine, resulting in the formation of des-Asn1-AMPA. The native enzyme was shortened by eight residues by cyanogen bromide cleavage at the single methionine residue. Although all modified proteins show a reduced affinity for monomeric lipids, they are easily saturated with micellar substrate analogs. Whereas the removal of the N-terminal octapeptide abolished all enzymatic activity the other modified enzymes possess a low (1%), but measurable enzymatic activity. It is concluded that chemical modifications in the N-terminal region give rise to a distortion of the active site, thus reducing the activity of the lipid-bound enzyme.
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PMID:Characterization of phospholipases A2 of Naja melanoleuca snake venom modified at the N-terminal region. 642 76

Photoaffinity labeling of the nicotinic acetylcholine receptor from Torpedo marmorata electric tissue was performed in the presence of cholinergic effectors in the millisecond to second time range by a combination of a stopped-flow apparatus and a high-energy pulse laser. The label applied was [3H]triphenylmethylphosphonium, a lipophilic cation previously shown to be a specific blocker of the acetylcholine receptor ion channel. With the receptor in the resting state most of the label was incorporated into the alpha polypeptide chains. In the presence of agonists and antagonists increasing incorporation into the delta- and (less pronounced) the beta-chain was observed. The time course of this increase had a half-life of about 0.4 s, being slower than receptor activation and channel opening. in the resting, active, and even rapidly desensitized state, the alpha polypeptide chains appear to be the primary targets of the photoaffinity reaction. The action spectrum of the photolabeling has a sharp maximum at lambda = 270 nm and a small-side maximum at lambda = 290 nm. It does not resemble the absorption spectrum of the label and may hint at amino acid side chains as the moieties activated by UV light causing the photolabeling. The effector specificity of the observed slow increase of label incorporation into the delta polypeptide chain was investigated. It does not prove that slow desensitization is the underlying event. The agonists acetylcholine and carbamoylcholine as well as treatment of receptor-rich membranes with phospholipase A2 (but not phospholipase D) triggered labeling of delta, but antagonists such as D-tubocurarine and most conspicuously flaxedil had a similar effect.
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PMID:Rapid laser flash photoaffinity labeling of binding sites for a noncompetitive inhibitor of the acetylcholine receptor. 646 10

The rotational mobility of band 3, a protein constituent of the human erythrocyte membrane, was measured by observing the flash-induced transient dichroism of the triplet probe eosin maleimide. In the presence of melittin, a pharmacologically active polypeptide from honey bee (Apis mellifera) venom, a dose-dependent loss of rotational mobility was detected. With acetylated melittin, the ability to immobilize is reduced. Succinylated melittin, however, is devoid of immobilizing activity. The possible relevance of these findings to the normal mode of action of melittin was examined by comparing the relative abilities of the native, acetylated and succinylated melittins to lyse erythrocytes and synergize with phospholipase A2, another constituent of bee venom. For both these properties, the order of effectiveness is native melittin greater than acetyl melittin greater than succinyl melittin = 0, the same as their order of effectiveness in immobilizing band 3. A mechanism is proposed in which melittin is anchored in the membrane by its hydrophobic N-terminus, while its cationic C-terminal moiety binds to negatively charged residues on membrane proteins. This leads either directly or indirectly to protein aggregation and hence loss of mobility. From a detailed comparison of the different effects of the melittin derivatives, it is concluded that melittin may function in vivo by aggregating membrane proteins in order to allow phospholipase A2 to gain access to the membrane bilayer and commence catalysis.
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PMID:The influence of melittin on the rotation of band 3 protein in the human erythrocyte membrane. 646 41


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