L-canavanine is a time-controlled mechanism-based inhibitor of Pseudomonas aeruginosa arginine deiminase.
The mechanism for inhibition of the Pseudomonas aeruginosa arginine deiminase (PaADI) by the arginine analogue l-canavanine was investigated. Inhibition by this substance (kinact = 0.31 +/- 0.03 min-1 and Ki = 1.7 +/- 0.5 mM) is associated with the formation of a modestly stable S-alkylthiouronium intermediate, detected by using kinetic techniques and identified by using electrospray ionization mass spectrometry. The electronic and/or orientation effects, caused by oxygen-for-methylene substitution in l-canavanine, on the rate of enzyme regeneration from the S-alkylthiouronium intermediate could serve as the basis for a strategy for the rational design of new slow substrate inhibitors of ADI.
Lu
Xuefeng
X
Department of Chemistry, University of New Mexico, Albuquerque, New Mexico 87131, USA.
Li
Ling
L
Feng
Xiaohua
X
Wu
Yan
Y
Dunaway-Mariano
Debra
D
Engen
John R
JR
Mariano
Patrick S
PS
D001120:Arginine / Q000737:chemistry; D002172:Canavanine / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D015394:Molecular Structure; D011550:Pseudomonas aeruginosa / Q000201:enzymology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D002172:Canavanine; D001120:Arginine; D006867:Hydrolases; C019723:arginine deiminase