α1-Antitrypsin is the prototypical member of the serine proteinase inhibitor or serpin superfamily of proteins. The family includes α1-antichymotrypsin, C1 inhibitor, antithrombin and neuroserpin, which are all linked by a common molecular structure and the same suicidal mechanism for inhibiting their target enzymes. Point mutations result in an aberrant conformational transition and the formation of polymers that are retained within the cell of synthesis. The intracellular accumulation of polymers of mutant α1-antitrypsin and neuroserpin results in a toxic gain-of-function phenotype associated with cirrhosis and dementia respectively. The lack of important inhibitors results in overactivity of proteolytic cascades and diseases such as COPD (chronic obstructive pulmonary disease) (α1-antitrypsin and α1-antichymotrypsin), thrombosis (antithrombin) and angio-oedema (C1 inhibitor). We have grouped these conditions that share the same underlying disease mechanism together as the serpinopathies. In the present review, the molecular and pathophysiological basis of α1-antitrypsin deficiency and other serpinopathies are considered, and we show how understanding this unusual mechanism of disease has resulted in the development of novel therapeutic strategies.
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June 2009
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Review Article|
May 14 2009
α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies
Ugo I. Ekeowa;
Ugo I. Ekeowa
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Bibek Gooptu;
Bibek Gooptu
†School of Crystallography, Birkbeck College, University of London, Malet Street, London WC1E 7HX, U.K.
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Didier Belorgey;
Didier Belorgey
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Peter Hägglöf;
Peter Hägglöf
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Susanna Karlsson-Li;
Susanna Karlsson-Li
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Elena Miranda;
Elena Miranda
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Juan Pérez;
Juan Pérez
‡Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Facultad de Ciencias, Campus de Teatinos, Málaga, 29071, Spain
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Ian MacLeod;
Ian MacLeod
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
§Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K.
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Heike Kroger;
Heike Kroger
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
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Stefan J. Marciniak;
Stefan J. Marciniak
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
§Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K.
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Damian C. Crowther;
Damian C. Crowther
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
§Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, U.K.
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David A. Lomas
*Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Cambridge CB2 0XY, U.K.
Correspondence: Professor David A. Lomas (email dal16@cam.ac.uk).
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Publisher: Portland Press Ltd
Received:
September 22 2008
Revision Received:
November 13 2008
Accepted:
November 28 2008
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2009 Biochemical Society
2009
Clin Sci (Lond) (2009) 116 (12): 837–850.
Article history
Received:
September 22 2008
Revision Received:
November 13 2008
Accepted:
November 28 2008
Citation
Ugo I. Ekeowa, Bibek Gooptu, Didier Belorgey, Peter Hägglöf, Susanna Karlsson-Li, Elena Miranda, Juan Pérez, Ian MacLeod, Heike Kroger, Stefan J. Marciniak, Damian C. Crowther, David A. Lomas; α1-Antitrypsin deficiency, chronic obstructive pulmonary disease and the serpinopathies. Clin Sci (Lond) 1 June 2009; 116 (12): 837–850. doi: https://doi.org/10.1042/CS20080484
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