Alpha-1-antitrypsin-structure, function and genetic variants
Salahuddin, P.
Indian Journal of Biochemistry and Biophysics 28(3): 164-167
1991
ISSN/ISBN: 0301-1208 PMID: 1786966 Document Number: 3768
It is possible to explain the acceleration of the onset of emphysema in the light of the current knowledge of structure and function of ɑ-1-antitrypsin. It has been suggested2 that lungs elasticity is maintained by a balance between destruction (by destructive enzymes, principally elastase) and protection (by proteinase inhibitors, principally ɑ-1-antitrypsin). In individuals deficient in ɑ-1-antitrypsin, the balance is disturbed towards destruction since the inhibitor concentration is not enough to protect the lower respiratory tract from its burden of neutrophil elastase. Cigarette smoking also contributes to the disruption of the fragile structures of the lower respiratory tract. Smoking results in increase in the leucocyte concentration and hence in increased exposure of lung tissues to neutrophil elastase. Further, cigarette smoke contains oxidants' which modify active centre methionine of ɑ-1-antitrypsin to methionine sulphoxide. The latter is too bulky to be accommodated into elastase pocket and therefore oxidative modification of the inhibitor abolishes its inhibitory activity. It would be interesting to have a mutant of oc-IAT with normal anti-elastase activity but resistant to oxidative stress. Val-mutant of ɑ-IAT is one such inhibitor that has been synthesised by recombinant DNA technique and has been successfully tested as an inhibitor of connective tissue breakdown in a model of inflammation. It holds promise for intravenous replacement therapy in patients with severe ɑ-IAT deficiency.
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