A Mutational Analysis of Residues in Cholera Toxin A1 Necessary for Interaction with Its Substrate,  the Stimulatory G Protein Gsα

Jobling, Michael G.; Gotow, Lisa F.; Yang, Zemin; Holmes, Randall K.

doi:10.3390/toxins7030919

Cited by 13 publications

(6 citation statements)

References 45 publications

(45 reference statements)

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“…For each of these events, the exact molecular mechanism remains to be determined and could involve a number of cellular effects. For example, an inhibition of cytosolic CTA1 activity could involve alterations to CTA1 interactions with Hsp90, ADP-ribosylation factors, Gsα, or lipid rafts [32–35,44]. It is also possible that a single compound could affect multiple steps of the intoxication process, such as the inhibition of both CTB surface binding and CTA1 cytosolic activity by EGCG.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Cholera Toxin and Other AB Toxins by Polyphenolic Compounds

et al. 2016

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Cholera toxin (CT) is an AB-type protein toxin that contains a catalytic A1 subunit, an A2 linker, and a cell-binding B homopentamer. The CT holotoxin is released into the extracellular environment, but CTA1 attacks a target within the cytosol of a host cell. We recently reported that grape extract confers substantial resistance to CT. Here, we used a cell culture system to identify twelve individual phenolic compounds from grape extract that inhibit CT. Additional studies determined the mechanism of inhibition for a subset of the compounds: two inhibited CT binding to the cell surface and even stripped CT from the plasma membrane of a target cell; two inhibited the enzymatic activity of CTA1; and four blocked cytosolic toxin activity without directly affecting the enzymatic function of CTA1. Individual polyphenolic compounds from grape extract could also generate cellular resistance to diphtheria toxin, exotoxin A, and ricin. We have thus identified individual toxin inhibitors from grape extract and some of their mechanisms of inhibition against CT.

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Section: Discussionmentioning

confidence: 99%

Inhibition of Cholera Toxin and Other AB Toxins by Polyphenolic Compounds

et al. 2016

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“…After ADP‐ribosylation by CT, the adenylate cyclase (AC) remains in its GTP‐bound state which enhances AC activity and increases the intracellular cAMP concentration. Higher levels of cAMP lead to an imbalance in electrolyte movement in epithelial cells, decreased sodium uptake and increased anion extrusion, mostly chloride, by cystic fibrosis trans‐membrane conductance regulator (CFTR) .…”

Section: Discussionmentioning

confidence: 99%

Sulphated Polysaccharide Isolated from the Seaweed Gracilaria caudata Exerts an Antidiarrhoeal Effect in Rodents

Costa

Araújo

Sousa

et al. 2016

Basic Clin Pharma Tox

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Diarrhoea is a significant health problem for children in developing countries that causes more than 1 million deaths annually. This study aimed to evaluate the antidiarrhoeal effect of sulphated polysaccharide (PLS) from the alga Gracilaria caudata in rodents. For the evaluation, acute diarrhoea was induced in Wistar rats (150-200 g) by administration of castor oil (10 mg/kg). Then, different parameters, including enteropooling and gastrointestinal transit and its pharmacological modulation by opioid and cholinergic pathways, were assessed using activated charcoal in Swiss Mice (25-30 g). Secretory diarrhoea was examined using cholera toxin (CT) (1 mg/loop)-treated, isolated intestinal loops from Swiss mice (25-30 g), which were also used to examine fluid secretion, loss of chloride ions into the intestinal lumen and absorption. In addition, a GM1-dependent ELISA was used to evaluate the interaction between PLS, CT and the GM1 receptor. Pre-treatment with PLS (10, 30 and 90 mg/kg) reduced faecal mass, diarrhoeal faeces and enteropooling. However, 90 mg/kg more effectively reduced these symptoms; therefore, it was used as the standard dose in subsequent experiments. Gastrointestinal transit was also reduced by PLS treatment via a cholinergic mechanism. Regarding the diarrhoea caused by CT, PLS reduced all study parameters, and the ELISA showed that PLS can interact with both the GM1 receptor and CT. These results show that PLS from G. caudata effectively improved the parameters observed in acute and secretory diarrhoea, which affects millions of people, and may lead to the development of a new alternative therapy for this disease.Seaweeds (marine macroalgae) are excellent sources of pharmacologically active compounds, and the number of substances isolated from seaweed sources has been generating a great deal of interest [1]. The structures of most isolated compounds have been determined, and the therapeutic potentials of these substances are currently being examined [2,3]. Investigations into the precise phytochemical composition of different seaweeds have revealed that they are principally composed of different types of sulphated polysaccharides and other potentially useful chemical biomolecules [4].Over the past several decades, it has become clear that sulphated polysaccharides are involved in numerous cellular processes and possess a range of pharmacological activities; therefore, they have attracted the attention of numerous research groups [5]. Sulphated polysaccharides are complex macromolecular compounds found in the extracellular matrix, and these polysaccharides are known to have anticoagulant, antiviral and anti-inflammatory activities that have potential applications as nutraceuticals, cosmetics and pharmaceuticals [6].In Brazil, several species of the genus Gracilaria, including Gracilaria caudata, thrive in coastal regions. We showed that G. caudata produces an agaran consisting of alternating residues of 3-linked-b-D-galactopyranose connected to either 4-linked-3,6-anhydro-a-L-galactopyr...

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“…In a mutagenesis study, residues outside of the active site were found to affect ADP-ribosylation of G sα , but not a small molecule guanidine substrate. 335 In addition, G sα is a poor substrate for CT-A1 on its own, but ADP-ribosylation is improved in the presence of G βγ . 336 Thus, the cholera toxin catalytic subunit undergoes allosteric activation by binding ARF6-GTP, increasing its general level of ADP-ribosylation activity, but activity against its target G sα is additionally dependent on very specific interactions with both the target and target-associated factors.…”

Section: Role Of Additionalmentioning

confidence: 99%

ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

et al. 2017

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Posttranslational modifications (PTMs) regulate protein functions and interactions. ADP-ribosylation is a PTM, in which ADP-ribosyltransferases use nicotinamide adenine dinucleotide (NAD) to modify target proteins with ADP-ribose. This modification can occur as mono- or poly-ADP-ribosylation. The latter involves the synthesis of long ADP-ribose chains that have specific properties due to the nature of the polymer. ADP-Ribosylation is reversed by hydrolases that cleave the glycosidic bonds either between ADP-ribose units or between the protein proximal ADP-ribose and a given amino acid side chain. Here we discuss the properties of the different enzymes associated with ADP-ribosylation and the consequences of this PTM on substrates. Furthermore, the different domains that interpret either mono- or poly-ADP-ribosylation and the implications for cellular processes are described.

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A Mutational Analysis of Residues in Cholera Toxin A1 Necessary for Interaction with Its Substrate, the Stimulatory G Protein Gsα

Cited by 13 publications

References 45 publications

Inhibition of Cholera Toxin and Other AB Toxins by Polyphenolic Compounds

Inhibition of Cholera Toxin and Other AB Toxins by Polyphenolic Compounds

Sulphated Polysaccharide Isolated from the Seaweed Gracilaria caudata Exerts an Antidiarrhoeal Effect in Rodents

ADP-Ribosylation, a Multifaceted Posttranslational Modification Involved in the Control of Cell Physiology in Health and Disease

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