The molecular structure and pathology ofα 1-antitrypsin

Abstract

Antitrypsin is the predominant protease inhibitor in human plasma. Despite its name, its prime function is an inhibitor of neutrophil elastase. It is the archetype of a family of protease inhibitors (serpins) characteristically with a MW 50,000 and a highly ordered tertiary structure. Its role is as a protector of vulnerable tissues against digestion by leukocyte enzymes, and plasma deficiency predisposes to premature emphysema. Northern Europeans are uniquely susceptible to deficiency due to the frequency of two mutants (Z & S) both having substitutions at glutamic acids that form key salt bridges in the molecule. In the reactive center of antitrypsin is a labile methionine which allows leucocytes to switch off inhibitory activity but this contributes to the accelerated lung degeneration in cigarette smokers. Although plasma replacement therapy is one option for treatment a first approach is to avoid smoking and other environmental irritants.