Theoretical Study of the Reduction Mechanism of Sulfoxides by Thiols

Abstract

Theoretical computations have been carried out to investigate the reaction mechanism of the sulfoxide reduction by thiols in solution. This reaction is a suitable model for enzymatic processes involving methionine sulfoxide reductases (Msrs). Recent investigations on the Msr mechanism have clearly shown that a sulfenic acid intermediate is formed on the catalytic cysteine of the active site concomitantly to the methionine product. In contrast, experimental studies for the reaction of a number of thiols and sulfoxides in solution did not observe sulfenic acid formation. Only, a disulfide was identified as the final product of the process. The present study has been carried out at the MP2/6-311+G(3d2f,2df,2p)//B3LYP/6-311G(d,p) level of theory. The solvent effect in DMSO has been incorporated using a discrete-continuum model. The calculations provide a basic mechanistic framework that allows discussion on the apparent discrepancy existing between experimental data in solution and in the enzymes. They show that, in the early steps of the process in solution, a sulfurane intermediate is formed the rate of which is limiting. Then, a proton transfer from a second thiol molecule to the sulfurane leads to the formation of either a sulfenic acid or a disulfide though the latter is much more stable than the former. If a sulfenic acid is formed in solution, it should react with a thiol molecule making its experimental detection difficult or even unfeasible.

Characterization of the Amino Acids from Neisseria meningitidis MsrA Involved in the Chemical Catalysis of the Methionine Sulfoxide Reduction Step

“…The methionine sulfoxide reductase step of the MsrA mechanism was previously shown to be very fast (1) and postulated to imply the formation of a sulfurane transition state of bipyramidal geometry on the basis of the theoretical chemistry study (6). According to these data, the reductase step should imply 1) the formation of an enzyme-substrate complex, 2) the deprotonation of Cys-51, 3) the involvement of an acid catalyst to protonate the sulfoxide substrate and favor the sulfurane-type transition state formation, and 4) the rearrangement of the sulfurane-type transition state to obtain Met and sulfenic acid.…”

“…An average of at least six runs was recorded for each AcMetSONHMe concentration. Rate constants, k obs , were obtained by fitting fluorescence traces with the monoexponential Equation 6 in which c represents the end point, a the amplitude of the fluorescence increase (Ͻ0), and k obs the rate constant.…”

“…Study of the reduction mechanism of dimethyl sulfoxide (Me 2 SO) by methanethiol in Me 2 SO solution has recently been investigated by quantum chemistry calculations (6). It was shown that 1) a sulfurane species is formed prior to formation of either a sulfenic acid intermediate or a disulfide species and 2) the rate-limiting step is governed by proton transfer between the thiol and the sulfoxide functions prior to sulfurane formation.…”

Characterization of the Amino Acids Involved in Substrate Specificity of Methionine Sulfoxide Reductase A

“…The catalytic mechanism is in agreement with the kinetic mechanism, which was shown to be of ping-pong type for both classes of Msrs (9, 10). Moreover, for both classes of Msrs, the overall rate-limiting step is associated with the Trxrecycling process, whereas the rate of formation of the intradisulfide bond is governed by that of the reductase step, the rate of which is fast (11,12).A theoretical study of the reduction mechanism of sulfoxides by thiols has been recently investigated by quantum chemistry calculations, which supports formation of a sulfurane intermediate (13). The amino acids involved in the catalysis of the reductase step of Neisseria meningitidis MsrA have also recently been characterized by molecular enzymology approaches (14).…”

“…A theoretical study of the reduction mechanism of sulfoxides by thiols has been recently investigated by quantum chemistry calculations, which supports formation of a sulfurane intermediate (13). The amino acids involved in the catalysis of the reductase step of Neisseria meningitidis MsrA have also recently been characterized by molecular enzymology approaches (14).…”