Characterization of competitive inhibitors for the transferase activity of Pseudomonas earuginosa exotoxin A

Souzan Armstrong, Jia He Li, Jie Zhang, A. Rod Merrill

Research output: Contribution to journalArticlepeer-review

12 Scopus citations


A series of small, nonpolar compounds were tested for their ability to inhibit the ADP-ribosyl transferase activity of Pseudomonas aeruginosa exotoxin A. The IC50 values for the compounds tested ranged from 87 nM to 484 μM for NAP and CMP12, respectively. It was demonstrated that NAP was a competitive inhibitor of the ADPRT reaction for the NAD+ substrate with a Ki of 45 ± 5 nM, which was in good agreement with the dissociation constant determined independently (KD = 56 ± 6 nM). The IC50 value for NAP was 87 ± 12 nM, which strongly correlated with the Ki and KD values. Furthermore, NAP was shown to noncovalently associate with the exotoxin A active site using exhaustive dialysis, NMR, and electrospray mass spectrometry. Finally, a computer molecular model using the X-ray structure of the substrate-bound toxin was generated with NAP bound to the active site of exotoxin A at the nicotinamide-binding site. This model is consistent with the X-ray structure of the catalytic domain of poly-ADP-ribose polymerase complexed with 4-amino-naphthalimide (Compound 4) that was included in this study.

Original languageEnglish (US)
Pages (from-to)235-246
Number of pages12
JournalJournal of Enzyme Inhibition and Medicinal Chemistry
Issue number4
StatePublished - Aug 2002
Externally publishedYes


  • ADP-ribosyl transferase
  • Computer molecular model
  • Pseudomonas aeruginosa exotoxin A

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • General Biochemistry, Genetics and Molecular Biology
  • Biochemistry


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