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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Bordetella pertussis, the causative agent of whooping cough, releases pertussis toxin in an inactive form. The toxin consists of an A protomer containing one S1 peptide subunit and a B oligomer containing several other peptide subunits. The toxin binds to cells via the B oligomer, and the S1 subunit is activated and expresses ADP-ribosyltransferase and NAD glycohydrolase activities. Treatment of purified toxin with dithiothreitol (DTT) in vitro increases both activities. ATP and the detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) synergistically reduce the A0.5 (activation constant) for DTT from greater than 100 mM to 200 microM. We studied the structure-activity relationships of activators of the toxin. In the presence of CHAPS (1%) and DTT (10 mM) the following compounds increased the NAD glycohydrolase activity of the toxin with the following A0.5's in microM and fraction of the ATP effect in parentheses: ATP, 0.2 (1.0); ADP, 6 (0.8); UTP, 15 (0.7); GTP, 35 (0.6); pyrophosphate, 45 (0.7); triphosphate, 60 (0.6); tetraphosphate, greater than or equal to 170 (greater than or equal to 0.4). Thus, the polyphosphate moiety is sufficient to stimulate the toxin, and the adenosine moiety confers upon ATP its extraordinary affinity for the toxin. Phospholipid and detergents could substitute for CHAPS in the activation of the toxin. Glutathione substituted for DTT with an A0.5 of 2 mM, a concentration within the range found in eucaryotic cells. Thus, membrane lipids and cellular concentrations of glutathione and ATP are sufficient to activate pertussis toxin without the need for a eucaryotic enzymatic process.
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PMID:Structure-activity analysis of the activation of pertussis toxin. 303 Mar 99

We have demonstrated earlier that V717G-APP(714-723), the membrane fragment of the V717G ("London") familial Alzheimer's disease (FAD) mutant of amyloid precursor protein (APP), is a potent stimulator of G-proteins in human brain membranes. In this study, we tested the hypothesis that Met-722 in the V717G-APP(714-723) peptide (P2) plays a critical role in the P2-induced oxidative stimulation of G-proteins in the human temporal cortex membranes and in the neurotoxicity of the peptide in differentiated PC12 and cerebellar granular cells. We found that 10 microM P3, the Met-722 sulfoxide analog of P2, produced a twofold lower stimulation of G-proteins ([(35)S]-GTPgammaS binding) in control temporal cortex membranes compared with 10 microM P2. The stimulatory effect of 10 microM P4, the Met-722 sulfone analog of P2, was 2.5-fold lower than the effect of P2. In Alzheimer's disease (AD) temporal cortex, the P3 and P4 stimulation of G-proteins was slightly weaker than the P2 stimulation. Substitution of the Met-722 S-atom in P2 by -CH(2)- group (P5) led to the disappearance of P2 stimulatory effect on G-proteins. Glutathione (GSH), melatonin (Mel), desferrioxamine (DFO) and 17-beta-estradiol (17betaE) significantly reduced P2 stimulatory effect on G-proteins in human brain. Only DFO and Mel were able to reduce the moderate stimulation of G-proteins by P3, whereas none of the tested antioxidants influenced the weak stimulation by P4. P2 at 100 microM induced a 40% decrease in PC12 cell viability as revealed by MTT assay, the effect being significantly higher than that of P3 or P4, whereas P1 (wild-type APP(714-723)) did not affect cell viability. Trypan Blue exclusion assay demonstrated that 10 microM P2 and P3 induced 3.8- and 3.5-fold death in the cerebellar granular cells as compared with the respective control values. P1 and P4 at 10 microM induced 1.7- and 2.3-fold increase in cell death, respectively. Treatment of the cerebellar granular cells with pertussis toxin decreased the high neurotoxicity of P2 and P3, whereas the low toxicity of P1 and P4 was not influenced. These results support the hypothesis that the G-protein stimulatory effect and neurotoxicity of "London"-mutated V717G-APP(714-723) (P2) and its Met-722 oxidized analogs involve oxidative-dependent and oxidative-independent mechanisms and the oxidation state of Met-722 plays a critical role in determining the mechanism.
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PMID:Critical role of methionine-722 in the stimulation of human brain G-proteins and neurotoxicity induced by London familial Alzheimer's disease (FAD) mutated V717G-APP(714-723). 1710 Dec 28