Quantitative structure-activity relationships for the pre-steady state of Pseudomonas species lipase inhibitions by p-nirophenyl-N-substituted carbamates.
The pre-steady states of Pseudomonas species lipase inhibitions by p-nitrophenyl-N-substituted carbamates (1-6) are composed of two steps: (1) formation of the non-covalent enzyme-inhibitor complex (E:I) from the inhibitor and the enzyme and (2) formation of the tetrahedral enzyme-inhibitor adduct (E-I) from the E:I complex. From a stopped-flow apparatus, the dissociation constant for the E:I complex, KS, and the rate constant for formation of the tetrahedral E-I adduct from the E:I complex, k2 are obtained from the non-linear least-squares of curve fittings of first-order rate constant (k(obs)) versus inhibition concentration ([I]) plot against k(obs)=k2+k2[I]/(KS+[I]). Values of pKS, and log k2 are linearly correlated with the sigma* values with the rho* values of -2.0 and 0.36, respectively. Therefore, the E:I complexes are more positive charges than the inhibitors due to the rho* value of -2.0. The tetrahedral E-I adducts on the other hand are more negative charges than the E:I complexes due to the rho* value of 0.36. Formation of the E:I complex from the inhibitor and the enzyme are further divided into two steps: (1) the pre-equilibrium protonation of the inhibitor and (2) formation of the E:I complex from the protonated inhibitor and the enzyme.
Lin
Gialih
G
Department of Chemistry, National Chung-Hsing University, Taichung, 402, Taiwan. gilin@dragon.nchu.edu.tw
Liao
Wei-Cheng
WC
Ku
Zu-Hsuan
ZH
D002219:Carbamates / Q000737:chemistry* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007700:Kinetics; D008049:Lipase / Q000037:antagonists & inhibitors*; D008956:Models, Chemical; D011549:Pseudomonas / Q000201:enzymology*; D021281:Quantitative Structure-Activity Relationship
D002219:Carbamates; D004791:Enzyme Inhibitors; D008049:Lipase