Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0043167 (pertussis)
 19,595 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pertussis toxin has been shown to be an important virulence factor and an antigen which will probably be essential to a pertussis vaccine. Inactivation of the pertussis toxin was required due to the pharmacological properties associated with this toxin. However, chemical inactivation has the potential of altering important epitopes or of failing to inactivate the toxin. Cloning and sequencing of the pertussis toxin operon has permitted the introduction of specific mutations in the S1 gene which have been shown to have a profound effect on the subsequent enzyme activity. Various mutations were constructed, re-assembled into the pertussis toxin operon and returned to the Bordetella pertussis chromosome for expression. Pertussis toxin, with lysine substituted for arginine at position 9 in the S1 subunit (PTA-K9) was assembled and expressed to wild type levels. Substitution of codons for aspartic acid, glycine and glutamine, for that of glutamic acid at position 129 were incorporated into the PTA-K9 construction. Virulence of these constructed B. pertussis strains and ADP-ribosylation by their toxoids were greatly reduced relative to that found with the wild type. Additionally, PTA-K9 was found to have reduced leukocytosis promotion and histamine sensitization activities. Finally, PTA-K9 was shown to be a protective immunogen in both intracerebral and aeorosol challenge assays.
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PMID:Construction and characterization of genetically inactivated pertussis toxin. 177 35

The bacterial exotoxins, cholera toxin (CT), pertussis toxin (PT), and diphtheria toxin (DT), interfere with specific host proteins to cause tissue damage for their respective infections. The common toxic mechanism for these agents is mono-ADP-ribosylation of specific amino acids in G(s)(alpha), G(i)(alpha), and eEF-2 proteins, respectively, by the catalytic A chains of the toxins (CTA, PTA, and DTA). In the absence of acceptor proteins, these toxins also act as NAD(+)-N-ribosyl hydrolases. The transition-state structures for NAD(+) hydrolysis and ADP-ribosylation reactions have oxacarbenium ion character in the ribose. We designed and synthesized analogues of NAD(+) to resemble their oxacarbenium ion transition states. Inhibitors with oxacarbenium mimics replacing the NMN-ribosyl group of NAD(+) show 200-620-fold increased affinity in the hydrolytic and N-ribosyl transferase reactions catalyzed by CTA. These analogues are also inhibitors for the hydrolysis of NAD(+) by PTA with K(i) values of 24-40 microM, but bind with similar affinity to the NAD(+) substrates. Inhibition of the NAD(+) hydrolysis and ADP-ribosyl transferase reactions of DTA gave K(i) values from 19 to 48 microM. Catalytic rate enhancements by the bacterial exotoxins are small, and thus transition-state analogues cannot capture large energies of activation. In the cases of DTA and PTA, analogues known to resemble the transition states bind with approximately the same affinity as substrates. Transition-state analogue interrogation of the bacterial toxins indicates that CTA gains catalytic efficiency from modest transition-state stabilization, but DTA and PTA catalyze ADP-ribosyl transferase reactions more from ground-state destabilization. pH dependence of inhibitor action indicated that both neutral and cationic forms of transition-state analogues bind to DTA with similar affinity. The origin of this similarity is proposed to reside in the cationic nature of NAD(+) both as substrate and at the transition state.
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PMID:Inhibitors of ADP-ribosylating bacterial toxins based on oxacarbenium ion character at their transition states. 1512 61