Alpha-1-proteinase inhibitors (α1PI) containing methionine (Met-358) or valine (Met➝Val-358) from recombinant yeast. The pure proteins were exposed to 1 of 4 different oxidizing systems: N-chlorosuccinimide (chemical oxidation), myeloperoxidase plus peroxide and halide (enzymatic oxidation), activated neutrophils (cellular oxidation), or gas-phase cigarette smoke. The effect of these treatments on the leukocyte elastase inhibitory function of both proteins was then assessed. After brief exposures, substantial inactivation of the normal inhibitor occurred, whereas the mutant inhibitor remained fully active. More prolonged exposures led to complete inactivation of the normal protein and partial inactivation of the mutant inhibitor. These results suggest that the reactive center methionyl residue in α1PI is more rapidly affected by oxidants than are other oxidizable residues in the inhibitor; however, Met-358 is not the only residue in α1PI whose modification can lead to the inactivation of the elastase inhibitory capacity of this protein.