Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.30 (PARP)
 13,611 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetically modified derivatives of cholera toxin (CT), harboring a single amino acid substitution in and around the NAD binding cleft of the A subunit, were isolated following site-directed mutagenesis of the ctxA gene. Two mutants of CT, designated CTS106 (with a proline-to-serine change at position 106) and CTK63 (with a serine-to-lysine change at position 63), were found to have substantially reduced ADP-ribosyltransferase activity and toxicity; CTK63 was completely nontoxic in all assays, whereas CTS106 was 10(4) times less toxic than wild-type CT. The mucosal adjuvanticity and immunogenicity of derivatives of CT were assessed by intranasal immunization of mice, with either ovalbumin or fragment C of tetanus toxin as a bystander antigen. Mice immunized with wild-type CT produced both local (immunoglobulin A in mucosal washes) and systemic immune responses to both CT and bystander antigens. CTS106 showed good local and systemic responses to bystander proteins and to itself. Interestingly, mice immunized with the nontoxic derivative of CT, CTK63, generated weak immune responses to the bystander antigens which were similar to those achieved when CT B subunit was used as an adjuvant. In parallel experiments, an equivalent nontoxic mutant of the Escherichia coli heat-labile enterotoxin, LTK63 (with a serine-to-lysine change at position 63), was tested (9). In contrast to CTK63, LTK63 was found to be more immunogenic and a better intranasal adjuvant than recombinant heat-labile enterotoxin B subunit or CTK63. This information, together with data on immunoglobulin subclass responses, suggests that although highly homologous, CT and heat-labile enterotoxin should not be considered biologically identical in terms of their ability to act as intranasal adjuvants.
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PMID:Intranasal immunogenicity and adjuvanticity of site-directed mutant derivatives of cholera toxin. 919 55

Escherichia coli heat-labile enterotoxin (LT) and cholera toxin (CT) were found to inhibit intracellular antigen processing. Processing was not inhibited by mutant LT with attenuated ADP-ribosyltransferase activity, CT B or LT B subunit, which enhanced presentation of preexisting cell surface peptide-class II major histocompatibility complex complexes. Inhibition of antigen processing correlated with A subunit ADP-ribosyltransferase activity.
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PMID:Inhibition of class II major histocompatibility complex antigen processing by Escherichia coli heat-labile enterotoxin requires an enzymatically active A subunit. 963 29

We provide compelling evidence that delivery of Ag in the absence of ADP-ribosylation can promote tolerance, whereas ADP-ribosyltransferase activity induces IgA immunity and prevents tolerance. By linking Ag to the ADP-ribosylating enzyme, cholera toxin subunit A1 (CTA1), we could show that the combination of targeting to antigen-presenting cells (APC) and enzymatic activity is a highly effective means of controlling the induction of tolerance or immunity. Firstly, we demonstrated that cholera toxin (CT), although potentially binding to all nucleated cells, in fact, bound preferentially to dendritic cells (DC) in vivo. Following injection of CT-conjugated Ag, we found that DC in the marginal zone (MZ) of the spleen accumulated Ag, a process that was GM1-ganglioside receptor dependent. Contrary to CTB, which also delivered Ag to the MZ DC, CT matured and activated co-stimulatory functions in the targeted DC and greatly augmented immune responses to Ag. Secondly, when Ag was incorporated into the CTA1-DD fusion protein, which equals the CT in adjuvant function but lacks GM1-ganglioside-binding ability, we greatly augmented specific responses to Ag. The DD-bound Ag was distinctly targeted to B cells and probably also to follicular dendritic cells (FDC) in vivo. Thus, in both constructs Ag was targeted to APC and associated with an ADP-ribosylating enzyme, which resulted in greatly enhanced immunogenicity. When the enzymatic activity was absent, as in CT B-subunit (CTB) or in the inactive CTA1R7K-DD mutant, Ag largely failed to stimulate an active immune response. Rather, this type of Ag exposure resulted in Ag-specific tolerance, especially when mucosal delivery of Ag was attempted. Therefore, targeting to APC in the absence or presence of the CTA1-enzyme appears to be an effective means to control tolerance and active protective IgA immunity.
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PMID:From toxin to adjuvant: basic mechanisms for the control of mucosal IgA immunity and tolerance. 1575 58