In human myeloperoxidase (MPO) the heme is covalently attached to the protein via two ester linkages and a unique sulfonium ion linkage between the sulfur atom of Met243 and the beta-carbon of the vinyl ring on pyrrole ring A. Here, we have investigated the variant Met243Val produced in Chinese hamster ovary cells in order to elucidate the role of the electron withdrawing sulfonium bond in compound I formation and reduction. Disruption of this MPO-typical bond causes a blue-shifted UV-vis spectrum and an increase in the heme flexibility. This had no impact on compound I formation mediated by hydrogen peroxide (2.2x10(7) M(-1)s(-1) at pH 7.0 and 25 degrees C). Compared with wild-type recombinant MPO the cyanide association rate with ferric Met243Val was significantly enhanced as were also the calculated apparent bimolecular compound I reduction rates by iodide (>10(8) M(-1)s(-1)) and thiocyanate (>10(8) M(-1)s(-1)). By contrast, the overall chlorination and bromination activities were decreased by 98.1% and 87.4%, respectively, compared with the wild-type protein. Compound I reduction by chloride was slower than compound I decay to a compound II-like species (0.4 s(-1)), whereas compound I reduction by bromide was about 10-times slower (1.3x10(4) M(-1)s(-1)) than the wild-type rate. These findings are discussed with respect to the known crystal structure of MPO and its bromide complex as well as the known redox chemistry of its intermediates and substrates.