Reaction of Glutathione with Conjugated Carbonyls

Abstract

Glutathione (GSH) reacts with conjugated carbonyls according to the equation: GSH + R - CH = CH - COR [.alpha.,.beta.-unsaturated aldehydes are reported to have pharmacological activity.] .dblarw. R - CH(SG) - CH2 - COR. The forward reaction follows 2nd order, the reverse reaction 1st order kinetics. It is assumed that this reaction reflects best the ability of conjugated carbonyls to inactivate sulfhydryl groups in biological systems. The rate of the forward reaction increases with pH approximately parallel with .alpha.SH. In addition to OH-, proton donors (e.g., buffers) also increase the rate. The catalytic effect of pH and buffer is interpreted in view of the reaction mechanism. The equilibrium constants as well as the rate constants for forward (K1) and reverse reaction show an extreme variation depending on the carbonyl structure. Acrolein and methyl vinyl ketone (k1 = 120 and 32 mo.-1 s-1, respectively) react more rapidly than any other carbonyl to give very stable adducts (half-lives for reverse reaction 4.6 and 60.7 days). Less reactive are 4-hydroxy-2-alkenals and 4-ketopenetenoic acid (k1 between 1 and 3 mol-1 s-1), but they also form very stable adducts with half-lives between 3.4-19 days. All other carbonyls studied react either very slowly (e.g., citral, ethyl crotonate, mesityl oxide, acrylic acid) or form very labile adducts (crotonal, pentenal, hexenal, 3-methyl-butenone). In comparing the biological activities of conjugated carbonyls, their reactivity towards HS (k1) and the stability of the adducts must be considered.