Studies on reactivity of human leukocyte elastase, cathepsin G, and porcine pancreatic elastase toward peptides including sequences related to the reactive site of .alpha.1-protease inhibitor (.alpha.1-antitrypsin)

McRae, B J; Nakajima, Kiichiro; Travis, James; Powers, James C.

doi:10.1021/bi00558a013

Cited by 99 publications

(52 citation statements)

References 27 publications

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“…These differences may be attributed to synergistic interactions between cathepsin G subsites, as shown for human chymase (40), and/or to the presence of PЈ residues in the intramolecularly quenched substrates. Earlier studies were done using peptide sequences derived from the RSL of ␣ 1 -antichymotrypsin (17) or ␣ 1 -proteinase inhibitor (41) to design cathepsin G substrates, but the kinetic parameters indicated that they were poorer substrates than those developed in this study, probably because of their short length, or lack of residues on the prime side.…”

mentioning

confidence: 73%

New, Sensitive Fluorogenic Substrates for Human Cathepsin G Based on the Sequence of Serpin-reactive Site Loops

Réhault¹,

Brillard-Bourdet²,

Juliano³

et al. 1999

Journal of Biological Chemistry

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confidence: 73%

New, Sensitive Fluorogenic Substrates for Human Cathepsin G Based on the Sequence of Serpin-reactive Site Loops

Réhault¹,

Brillard-Bourdet²,

Juliano³

et al. 1999

Journal of Biological Chemistry

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“…In regards to the question whether primary sequence differences among a 1 AT molecules can result in alteration of its function as an inhibitor for neutrophil elastase, it is known that changes in the region of the Met358-Ser959 active site have been shown to modify the function ofthe molecule (61). There is one human example of this: a 1 AT Pittsburgh, a molecule identical to Ml except for a substitution of Met358 to Arg358, a substitution that not only renders the molecule inefficient as an inhibitor of neutrophil elastase but also converts it into an efficient equivalent of antithrombin III (62).…”

Section: Discussionmentioning

confidence: 99%

Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase.

Ogushi¹,

Fells²,

Hubbard³

et al. 1987

J. Clin. Invest.

199

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Alpha 1-antitrypsin (alAT) deficiency resulting from homozygous inheritance of the Z-type alAT gene is associated with serum alAT levels of < 50 mg/dl and the development of emphysema in the third to fourth decades. Despite the overwhelming evidence that the emphysema of PiZZ individuals develops because of a "deficiency" of alAT and hence an insufficient antineutrophil elastase defense of the lung, epidemiologic evidence has shown that levels of alAT of only 80 mg/dl protect the lung from an increased risk of emphysema. With this background, we hypothesized that homozygous inheritance of the Z-type may confer an added risk beyond a simple deficiency of alAT by virtue of an inability of the Z-type alAT molecule to inhibit neutrophil elastase as effectively as the common Ml-type molecule. To evaluate this hypothesis, the functional status of alAT from PiZZ individuals (n = 10) was compared with that of alAT from PiMlMl individuals (a = 7) for its ability to inhibit neutrophil elastase (percent inhibition) as well as its association rate constant for neutrophil elastase (K association). Plasma alAT concentration, measured by radial immunodiffusion, was 34±1 mg/dl in PiZZ patients vs. 237±14 mg/dl for PiMlMl plasma, a sevenfold difference. When titrated against neutrophil elastase, the present inhibition of PiZZ plasma was significantly less than Pi MIMl plasma (ZZ 78±1% vs. MlMl 95±1%, P < 0.001) as was purified Z type alAT (ZZ, 63±2% vs. MlMl 86±2%, P < 0.001). Sodium dodecyl sulfate (SDS) gel comparisons of the complexes formed with Ml-type alAT and Z-type alAT with elastase demonstrated the Z alAT-elastase complexes were less stable than the Ml alAT-elastase complexes, thus releasing some of the enzyme to continue to function as a protease. Consistent with these observations, the K association of purified Z-type alAT for neutrophil elastase was lower than that of Ml-type alAT (ZZ 4.5±0i3 X 106 M-1s-' vs. MlMl 9.7±OA X 106 M-Is-1, P < 0.001), suggesting that for the population of alAT molecules, the active Z-type molecules take more than twice as long as the active Ml-type alAT to inhibit neutrophil elastase. Consequently, not only is there less alAT in PiZZ individuals, but the population of Z-type alAT molecules is less competent as an inhibitor of neutrophil elastase than Ml-type alAT molecules. This combination of defects suggests that PiZZ individuals have far less functional antielastase protection than suggested by the reduced concenAddress reprint requests to Dr. Crystal, Pulmonary Branch, Building

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“…The specificity of NSPs has been investigated using chromogenic (p-nitroanilide, Anb 5,2 -NH 2 , thiobenzylester) and fluorogenic [aminomethylcoumarin, fluorescence resonance energy transfer (FRET)] substrates (Castillo et al, 1979;Nakajima et al, 1979;McRae et al, 1980;Tanaka et al, 1985;Brubaker et al, 1992;Kam et al, 1992;Réhault et al, 1999;Wysocka et al, 2007;Korkmaz et al, 2008a;Carmona et al, 2009) (Fig. 4B).…”

Section: Structural Characteristics and Proteolytic Specificitymentioning

confidence: 99%

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

et al. 2010

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Studies on reactivity of human leukocyte elastase, cathepsin G, and porcine pancreatic elastase toward peptides including sequences related to the reactive site of .alpha.1-protease inhibitor (.alpha.1-antitrypsin)

Cited by 99 publications

References 27 publications

New, Sensitive Fluorogenic Substrates for Human Cathepsin G Based on the Sequence of Serpin-reactive Site Loops

New, Sensitive Fluorogenic Substrates for Human Cathepsin G Based on the Sequence of Serpin-reactive Site Loops

Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase.

Neutrophil Elastase, Proteinase 3, and Cathepsin G as Therapeutic Targets in Human Diseases

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