Conformational and Functional Polymorphism of Alpha1-Antitrypsin: Role in Health and Diseases

Sabina Janciauskiene
Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany
Sabine Wrenger
Tobias Welte
Ravi Mahadeva

Series: Protein Biochemistry, Synthesis, Structure and Cellular Functions
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Volume 10

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Special issue: Resilience in breaking the cycle of children’s environmental health disparities
Edited by I Leslie Rubin, Robert J Geller, Abby Mutic, Benjamin A Gitterman, Nathan Mutic, Wayne Garfinkel, Claire D Coles, Kurt Martinuzzi, and Joav Merrick

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Serpins (SERine Proteinase INhibitors) constitute part of the enzymatic regulatory mechanism in inflammation by inhibiting the activity of serine and cysteine proteases derived from inflammatory cells and tissue sources. Many circulating serpins are acute phase proteins; therefore, their role in the establishment of host defense may also depend on the magnitude and rapidity of changes in their concentrations and biological activity. Recently it has become apparent that a single serpin expresses multifunctional activities, and that some of these activities are dependent on the molecular form. Alterations of the serpin molecule that affect its structure and/or secretion and thereby reduces its functional levels, may favor pathological processes associated with chronic inflammation.

SERPINA1, á1-antitrypsin (AAT) is the prototypic member of the serpin super family and one the most abundant endogenous serine protease inhibitors in the circulation. The clinical importance of AAT is highlighted in individuals with inherited AAT deficiency who exhibit an increased susceptibility to the development of an early onset pulmonary emphysema, chronic bronchitis, bronchiestasis, and/or liver diseases. We propose that some individuals may exhibit acquired deficiency of AAT due to protein post-synthetic modifications (e.g. oxidation, nitrosylation, polymerization and cleavage), and that modified forms of AAT may have potent biological activities and contribute to inflammatory processes. Indeed, novel studies are expanding the link between deficiency of AAT and human diseases. Associations are shown between reduced AAT levels and HIV type 1 infection, hepatitis C infection, diabetes mellitus, systemic vasculitis and necrotizing panniculitis.

The altered forms of AAT are detected in tissues and fluids recovered from inflammatory sites, but the important questions of how they are generated, what their biological activities are, and which of them are directly linked to pathological processes and/or may be useful markers to characterise disease states, remain to be answered. A comprehensive understanding of serpin properties and functional mechanisms will have a bearing on our understanding and treatment of pathologies arising from both natural point mutations and from post-synthetically modified byproducts of serpins. Since serpins are so widely distributed and play important roles in critical physiological processes, therapies based on fundamental knowledge may have broad applications. The serpins themselves may become therapeutic tools for the delivery and uptake of drugs, if their biochemical properties can be manipulated successfully. (Imprint: Nova)

Abstract

Chapter 1. DISCOVERY OF ALPHA1-ANTITRYPSIN AND ITS
CLINICAL IMPORTANCE

Chapter 2. GENETIC VARIANTS

Chapter 3. SYNTHESIS AND REGULATION

Chapter 4. PROTEASE INHIBITORY ACTIVITY

Chapter 5. DIVERSE BIOLOGICAL ACTIVITIES

Chapter 6. CELLULAR INTERNALIZATION AND DEGRADATION

Chapter 7. STRUCTURE AND FUNCTION RELATIONSHIP

Chapter 8. GLYCOLYLATION

Chapter 9. CLEAVAGE

Chapter 10. OXIDATION AND NITROSYLATION

Chapter 11. COMPLEX FORMATION AND POLYMERIZATION

Chapter 12. AUGMENTATION THERAPY WITH ALPHA1-ANTITRYPSIN

CONCLUSION

REFERENCES

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