Function of a rare variant of alpha-1-antitrypsin, phenotype P(i) EFranklin S, a poor inhibitor of human neutrophil elastase.
A 31-year-old woman with the rare alpha-1-antitrypsin (A1AT) phenotype P(i) EFranklin S presented to this laboratory. Since little is known about the EFranklin protein, a study was established to investigate the biochemical properties of this glycoprotein, notably its inhibitory activity against human neutrophil elastase (HNE), compared with that of the more common A1AT variants M and Z. The serum A1AT level of 1.8 g/l (reference range 0.8-2.2 g/l) and anti-neutrophil elastase capacity (ANEC) value of 28 microM (reference range 15-42 microM) of this variant were normal. However, the association rate constant (AC) of the isolated and purified EFranklin protein 2.7 (0.4) x 10(6) M-1 s-1 at 25 degrees C was significantly lower compared with that in the normal M variant 9.1 (0.9) x 10(6) M-1 s-1. This implies that this form of A1AT is expressed at normal levels in serum but is functionally impaired as an inhibitor of HNE. The in vivo serum inhibition time of HNE was estimated to be 66 ms for the purified EFranklin protein compared with 20 ms for the M protein. While this protein is not an efficient inhibitor of HNE, there are sufficient molecules in the serum to achieve 100% inhibition of HNE and to protect the lung against proteinase attack. In conclusion, individuals who inherit the rare EFranklin variant in conjunction with the M or S A1AT molecules do not appear to have a high risk for the development of emphysema.
Cook
L
L
Department of Chemical Pathology, St. Vincent's Hospital Melbourne, Fitzroy, Victoria, Australia.
Knight
K R
KR
Burdon
J G
JG
Brenton
S
S
Hunt
J M
JM
D000328:Adult; D004591:Electrophoresis, Polyacrylamide Gel; D004646:Emphysema / Q000201:enzymology; D005260:Female; D006801:Humans; D007525:Isoelectric Focusing; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009504:Neutrophils / Q000201:enzymology*; D010641:Phenotype; D015842:Serine Proteinase Inhibitors / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000302:isolation & purification / Q000502:physiology*
D015842:Serine Proteinase Inhibitors; D000515:alpha 1-Antitrypsin; D019272:Leukocyte Elastase