A genetically engineered, mutant human alpha-1-proteinase inhibitor is more resistant than the normal inhibitor to oxidative inactivation by chemicals, enzymes, cells, and cigarette smoke.
Alpha-1-proteinase inhibitors (alpha 1PI) containing methionine (Met-358) or valine (Met----Val-358) at the reactive center were synthesized in and purified to homogeneity 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 alpha 1PI is more rapidly affected by oxidants than are other oxidizable residues in the inhibitor; however, Met-358 is not the only residue in alpha 1PI whose modification can lead to the inactivation of the elastase inhibitory capacity of this protein.
D001665:Binding Sites; D001798:Blood Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D010084:Oxidation-Reduction; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D009195:Peroxidase / Q000494:pharmacology; D010545:Peroxides / Q000494:pharmacology; D010947:Plants, Toxic; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012906:Smoke; D013388:Succinimides / Q000494:pharmacology; D014026:Nicotiana; D000515:alpha 1-Antitrypsin
D001798:Blood Proteins; D010545:Peroxides; D011994:Recombinant Proteins; D012906:Smoke; D013388:Succinimides; D000515:alpha 1-Antitrypsin; C015752:N-chlorosuccinimide; D009195:Peroxidase; D010196:Pancreatic Elastase