Chapter 20. Proteinases in Inflammation

Cysteine Proteases and Their Inhibitors

“…Proteins can be degraded down to amino acids in the lysosomes by interaction of both endo- and exopeptidases. , Due to the high concentrations of cathepsins in the lysosomes (10−40 mg/mL), , it is understandable that the cell has to protect itself from this enormous hydrolytic potential. The cell is successful in this respect because although cathepsins have activity for synthetic substrates at neutral pH, the enzymes are autolyzed or denatured in the physiological conditions of the cytosol, , and they are also controlled by specific inhibitors in the cytosol and the extracellular space 137 (section 6). In addition to this nonspecific protein degradation, cathepsins may play a role in specific processing of proteins, e.g.…”

“…A common factor in both of these processes is that the equilibrium between lysosomal enzymes released by macrophages or neutrophilic granulocytes and their endogenous inhibitors in the extracellular space is disturbed . This imbalance may originate from reduced inhibitor activity (proteolytic degradation by lysosomal enzymes; ,, inactivation by reactive oxygen species, which are produced by reduction of H 2 O 2 catalyzed by a myeloperoxidase released by neutrophilic granulocytes; ,, saturation of the inhibitors by excess release of lysosomal enzymes; , a change in the binding properties of the inhibitors and thus easier dissociation of the enzymes from the enzyme−inhibitor complexes 168 ) and/or increased stability of lysosomal cathepsins which are normally inactive in the extracellular space (protection of the enzyme from inactivation by binding to membrane systems of the cell; creation of microenvironments with low pH by the inflammation process). Free lysosomal proteases, in particular the neutrophilic elastase and cathepsin G, inactivate plasma factors, proteinase inhibitors, immunoglobulins, and transport proteins by non-substrate-specific, uncontrolled proteolysis and thereby destroy proteins of the cell membrane and of connective and supportive tissues.…”

Catalysis in Drug Design and Medicinal Chemistry

“…The association of emphysema with smoking is well-known, yet it is only recently that biochemical studies have led to a better understanding of the disease and the formulation of a working hypothesis related to its etiology and pathophysiology. The proteinase/antiproteinase imbalance hypothesis states that damage to lung connective tissue results from the migration of neutrophils to the lungs during infection or inflammation, and the subsequent release of proteolytic enzymes (proteinases) (Krantz, 1993). Inadequate control of the activity of these enzymes because of depressed levels of their physiological inhibitors (antiproteinases) leads to a proteinase/antiproteinase imbalance in the lungs, ultimately allowing the degradation of elastin, the elastic component of lung tissue, by proteinases (Birrer, 1993).…”

Cyclic Ketone Inhibitors of the Cysteine Protease Cathepsin K

“…The proteolytic processing of endogenous peptide substrates by cysteine proteases has been implicated in the pathology of a wide variety of diseases . These diseases include inflammation, tumor progression, parasitic infections, and osteoporosis . Cathepsin K (EC 3.4.22.38), a 24-kDa cysteine protease of the papain superfamily, is selectively and abundantly expressed within osteoclasts .…”