Kinetic characterisation of alpha-1-antitrypsin F as an inhibitor of human neutrophil elastase.
Patients homozygous for the Z allele of alpha-1-antitrypsin (alpha 1AT) have very low serum levels and are predisposed to emphysema. There have also been reports of emphysema being associated with the heterozygous phenotype FZ. To investigate whether F alpha 1AT was dysfunctional, the inhibitory activity of F alpha 1AT against human neutrophil elastase (HNE) was compared with that of common alpha 1AT phenotypes. Time-dependent inhibition of HNE by alpha 1AT was used to calculate the association rate constant (k assoc) for M, MZ, FM, FZ, F (partially purified from FZ or FS), Z and S alpha 1AT phenotypes in human sera. The results for k assoc at 25 degrees C were 9.1 (SD 0.9), 9.7 (SD 0.9), 8.0 (SD 0.8), 4.0 (SD 0.4), 4.2 (SD 0.8), 5.1 (SD 0.6) and 8.6 (SD 0.6) x 10(6) M-1s-1 respectively. F was found to have reduced activity much like that of Z, the alpha 1AT most commonly associated with emphysema. MZ (low risk for disease) and FZ heterozygotes had similar intermediate alpha 1AT levels. However the in vivo inhibition time for FZ was almost three times longer than for MZ, indicating greater exposure to proteolytic damage from free elastase for FZ than MZ individuals. In conclusion, F alpha 1AT is expressed in serum at low normal levels but is dysfunctional in its ability to inhibit HNE. Individuals who coinherit the F and a deficiency allele such as Z or Null, are likely to have a high risk for the development of emphysema. The disease risk for F homozygotes remains to be determined.
Department of Chemical Pathology, St Vincent's Hospital, Melbourne, Vic.
L
L
Cook
J G
JG
Burdon
S
S
Brenton
K R
KR
Knight
E D
ED
Janus
D000328:Adult; D000483:Alleles; D004247:DNA / Q000032:analysis; D004646:Emphysema / Q000378:metabolism*; D005260:Female; D006801:Humans; D007525:Isoelectric Focusing; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D000515:alpha 1-Antitrypsin / Q000378:metabolism*
D000515:alpha 1-Antitrypsin; D004247:DNA; D019272:Leukocyte Elastase