Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Escherichia coli heat-stable enterotoxins (ST) are classified into STa and STb according to their physicochemical and biologic characteristics. STa induces diarrhea, activating the guanylate cyclase-cGMP system. ST-like enterotoxins can be produced by bacteria other than E. coli, including Klebsiella pneumoniae. A Klebsiella ST has previously been shown to share some chemical and immunologic characteristics with E. coli ST. Aiming to define better the nature of Klebsiella ST, we have screened 237 children with diarrhea and 179 controls for ST-producing Klebsiella, using the SMA. We detected 26 Klebsiella strains from patients, two of which were positive in the SMA, and 36 from controls, all negative for ST. A partial purification was performed using an acetone precipitation followed by ultrafiltration and gel filtration techniques. Klebsiella toxin was heat-stable, methanol-soluble, sensitive to mercaptoethanol, active at acid pH values, but not at pH greater than 8. The time course of Klebsiella toxin in the SMA resembled that of E. coli STa. Klebsiella ST caused reduced Na absorption and net Cl secretion in rabbit ileal mucosa mounted in Ussing chambers. It was found to increase the cGMP but not the cAMP concentration. Finally, Klebsiella ST did not react with anti-E. coli STa MAb in a competitive ELISA. We conclude that K. pneumoniae may induce diarrhea through the production of an STa similar but not identical to E. coli STa.
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PMID:Characteristics and mechanism of action of a heat-stable enterotoxin produced by Klebsiella pneumoniae from infants with secretory diarrhea. 247 15

Certain enteropathogenic bacteria, including strains of Escherichia coli, Klebsiella pneumoniae and Yersinia enterocolitica, elicit their diarrhoeagenic effects by elaborating small molecular weight, heat-stable enterotoxins (STs). Structural and functional characteristics indicate that ST peptides are heterogeneous and two major subtypes, STa and STb, have been identified. Molecules of STa, unlike those of STb, are methanol-soluble and elicit their pathogenic effects by activating host cell guanylate cyclase activity and thereby increasing tissue cyclic GMP content: this increase in cyclic GMP causes fluid secretion. STa binds to specific proteinaceous receptors on intestinal cells but the nature of STa-receptor coupling to guanylate cyclase is poorly understood. The actions of STa, including binding to its receptor, activation of guanylate cyclase and stimulation of electrolyte transport, are rapid, reversible and tissue-specific. STa activates only particulate and not soluble guanylate cyclase. It alters the Vmax but not the apparent Km of this enzyme for Mg-GTP or Mn-GTP. At concentrations above 0.5-1 mM, calcium inhibits the STa activation of guanylate cyclase. The effects of calmodulin antagonists such as chlorpromazine on the activation of guanylate cyclase by STa are less clear. Inhibitors of phospholipid and arachidonic acid cascade pathways interfere with both basal and STa-stimulated guanylate cyclase. Membrane integrity is essential for STa activation of guanylate cyclase and the STa-receptor complex may activate the enzyme by intramembrane protein-protein interactions and/or perturbations. Interference with membrane phospholipid could alter such coupling.
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PMID:Toxins which activate guanylate cyclase: heat-stable enterotoxins. 286 Oct 70

Recent studies have added important new information to our understanding of the pathogenesis and ethiology of diarrheal disease. Vibrio cholerae produces a heat-labile enterotoxin, affecting cyclic AMP. A very similar heat-labile enterotoxin is produced also by certain strains of Escherichia coli, as well as by Citrobacter, Klebsiella, and Aeromonas. E. coli may also produce a heat-stable enterotoxin, stimulating guanylate cyclase activity. In order to produce the pathologic effects, E. coli first attaches to epithelial cells of the intestinal tract by means of pili or surface antigens. Enterotoxin can be demonstrated by both in vivo and in vitro tests, but none are yet suitable for routine diagnostic laboratories. A third mechanism whereby E. coli causes diarrheal disease consists of enteroinvasiveness. Campylobacter, Yersinia, and Clostridium difficile have been added to the list of enteric pathogens of man.
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PMID:Enteropathogenicity: recent developments. 612 11

Heat-stable enterotoxins (STs) are 18- or 19-amino acid peptides (STa or ST1) produced by enteropathogenic bacteria with small differences in their amino acid sequence and a highly conserved carboxy terminus. All STs contain a core of three disulfide bridges whose integrity is believed to be necessary for full biologic activity. We previously reported that strains of Klebsiella pneumoniae transformed by the plasmid pSLM004 produce a modified toxin not recognized by MAb raised against genuine Escherichia coli ST. Investigation of the chemical structure of the modified toxins revealed that three new toxins were present. These were purified to homogeneity by a series of sequential chromatography on reverse-phase columns using guanylate cyclase to monitor the enterotoxic activity during purification procedures. The sequence of the modified toxins was obtained by a combination of Edman degradation and mass spectrometry, showing that they are proteolytically processed forms of E. coli ST1b. In particular, toxin A-2 lacks the cysteine at position 18 and then is not able to form the disulfide bridge cysteine-10-cysteine-18. All three toxins showed the ability to stimulate guanylate cyclase and to elicit chloride secretion in Caco-2 cell monolayers mounted in Ussing chambers. Toxin A-1 and toxin B demonstrated greatly reduced immunoreactivity whereas toxin A-2 was not recognized at all in the ELISA. It is likely that the three modified toxins were generated by Klebsiella specific proteolytic processing of the original pretoxin. These results have important implications for the diagnosis and prevention of heat-stable toxin-induced diarrhea.
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PMID:Structural and functional features of modified heat-stable toxins produced by enteropathogenic Klebsiella cells. 1104 92