Molecular interactions in intermediate and transition states in the self-stimulated inhibition of enzymes.
Di-isopropyl fluorophosphate (DFP) and other organophosphorus inhibitors recruit the catalytic power of their target enzymes: the enzyme catalyzes its own irreversible phosphorylation. The magnitude of the catalytic acceleration can approach the factor by which the enzyme catalyzes its own acylation by natural substrates. The reaction of DFP with five serine proteases [chymotrypsin, elastase, dipeptidyl peptidase IV (DP IV), subtilisin and thermitase] exhibits in all cases the same pH dependence as does enzyme acylation by natural substrates. Chymotrypsin and elastase form a "fast" class of enzymes which react about ten-fold faster than the other three "slow" enzymes. All enzymes show k(HOH)/k(DOD) of about 2 but the proton inventory indicates one-proton character for "slow" enzymes and multiproton character for "fast" enzymes. Enthalpies of activation are about 33 kJ/mol (subtilisin, "slow") and 10 kJ/mol (elastase, "fast"). Entropies of activation are about -120 J.T-1.mol-1 (subtilisin, "slow") and -175J.T-1.s-1 (elastase, "fast"; T = temperature in K).
Demuth
H U
HU
Department of Drug Biochemistry, Martin Luther University, Halle-Wittenberg, GDR.
Heins
J
J
Fujihara
H
H
Mordy
C W
CW
Barth
A
A
Schowen
R L
RL
D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007531:Isoflurophate / Q000494:pharmacology; D007700:Kinetics; D011522:Protons; D013696:Temperature; D013816:Thermodynamics
D004791:Enzyme Inhibitors; D011522:Protons; D007531:Isoflurophate