Proteinase inhibitors inactivation

Several proteinase inhibitors inactivate the proteinases of the contact phase. Among the SERPINS are C-1 inactivator, O 1-proteinase inhibitor, and antithrombin. The target proteinases for these inhibitors are factor Xlla, kallikrein, and factor XIa. The molecular mechanisms are the same as those described for the procoagulant and fibrinolytic system proteinases. 

KROGDAHL A, HOLM H (1981) Soybean proteinase inhibitors and human proteolytic enzymes selective inactivation of inhibitors by treatment with human gastric juice. /M/fr. Ill 2045-51. 

Desrochers, P.E. and Weiss, S.J. (1988). Proteolytic inactivation of alpha-l-proteinase inhibitor by a neutrophil metalloproteinase. J. Clin. Invest. 81, 1646-1650. 

Some legumes, including raw soy or peanut flour are known to contain certain antinutritional factors such as proteinase inhibitors and hemagglutinins or lectins (21,22). These factors can be inactivated, for the most part, by moist heat, during processing. Interestingly, peanut flour contained more trypsin inhibitor and lectin than did soy flour (22). 

To prevent self-digestion, the pancreas releases most proteolytic enzymes into the duodenum in an inactive form as proenzymes (zymogens). Additional protection from the effects of premature activation of pancreatic proteinases is provided by proteinase inhibitors in the pancreatic tissue, which inactivate active enzymes by complex formation (right). 

Moreno J. J. and Pryor W. A. (1992). Inactivation of alpha 1-proteinase inhibitor by peioxynitrite. Chem. Res. Toxicol. 5 425-431. 

B. Wallaert, B. Grassier, C. Aerts, C. Mixon, C. Voian, and J. Mixon, Oxidative inactivation of txi-proteinase inhibitor by alveolar macrophages from healthy smokers requires die presence of myeioperoxyoase. Am. J. Respir. Ceil Mol huh. j 437 (1991). 

D. A. Johnson, A. J. Banctt, and R. W. Masco. Calhqwln L inactivates cti-proteinase inhibitor by cleavage In die active site region J. BioL Chem 267 14748 (1986). 

Ansari GAS, Gan JC, Barton BK. 1988. Synergistic inactivation of plasma alpha-proteinase inhibitor by aldehydes of cigarette smoke with styrene oxide and 1,2-dichloroethane. Arch Environ Cont Toxicol 17 533-536. 

Hypochlorite, released from inflammatory cells, can induce the inactivation of a i-antiproteinase by oxidising a crucial methionine residue at the active centre of the enzyme. Inactivation of the a j-proteinase inhibitor may allow proteases... 

The sensitivity of many serine-protease inhibitors (serpins) to ROIs has been determined in a number of groups and is summarized in Table 2. Of these serine-protease inhibitors, the most sensitive to inactivation by oxidants like OC1- or chloramines are those which contain methionine at or juxtaposed to the reactive centre [49] (e.g. plasminogen activator-inhibitor-1 (PAI-1), oq-proteinase inhibitor and 0(2-antiplasmin). Inactivation is thought to principally be due to the oxidation of these methionine residues to methionine sulfoxide [50-52]. PAI-1, which is rapidly inactivated in plasma, is also extremely sensitive to oxidants like iV-chlorosuccinimide, chloramine-T and H2O2, through a reaction involving oxidation of the reactive-site methionine. 

Since aiAT represents the archetype for the serpin (serine-proteinase inhibitor) superfamily of proteins, it is possible that similar oxidative or proteolytic mechanisms may function in the inactivation of other serpins that are important in controlling the inflammatory cascade. Some serpins contain a readily oxidised reactive-centre methionine residue (e.g. plasminogen activator-inhibitor [108] and a2-antiplasmin [109]), whilst all serpins (including antithrombin III [110] and protease nexin I [111]) contain an exposed loop which is susceptible to cleavage by proteinases. 

The ai -PI (along with other serum proteinase inhibitors) can attenuate lymphocyte antigen processing by binding to lymphocyte surface proteinases and subsequently down-regulate lymphocyte proliferative response. Therefore, oxidation of ai -PI may activate local immune response in sites of bacterial invasion and contribute to the development of the inflammatory process (B8, B9, S59). On the other hand, oxidative inactivation of some neutrophilic lysosomal enzymes can... 

Mil. Matheson, N. R., Wong, P. S., and Travis, J., Enzymatic inactivation of human alpha-1-proteinase inhibitor by neutrophil myeloperoxidase. Biochem. Biophys. Res. Commun. 88, 402-409 (1979). 

In particular, excessive proteolysis of elastin by HLE has been implicated in pulmonary emphysema [19]. In this case, the imbalance appears to result from reduced levels of active extracellular alpha,-proteinase inhibitor (a,-PI), the primary plasma inhibitor of HLE. This decrease is caused either by a genetic disorder (PiZZ phenotype individuals) or by reduction in the elastase inhibitory capacity (EIC) of ai-PI due to its oxidative inactivation by tobacco smoke [20]. The detailed evidence supporting the potential role of elastase in the development of emphysema has been extensively reviewed [21] and will not be repeated here. The fact that HLE is also a potent secretagogue [22] may play a role in several disease states, including cystic fibrosis [23], chronic bronchitis [24], and acute respiratory distress syndrome (ARDS) [25]. The mechanism of the secretagogue activity is not known, but, since the HLE-induced secretion can be blocked by specific HLE inhibitors, it appears to require catalytic activity by the enzyme [26]. 

Hall, P. Roberts, R. Methionine oxidation and inactivation of ai-proteinase inhibitor by Cu and glucose. Biochim. Biophys. Acta 1992, 1121, 325-330. 

In the body, enzymes are compartmentalized and function under highly restricted conditions. Some enzymes (e.g., proteinases) are not substrate-specific. When present in active form in an inappropriate part of the body, they act indiscriminately and cause considerable damage to the tissue. Inhibitors inactivate these enzymes at sites where their action is not desired. Proteinase inhibitors, which are themselves proteins, are widely distributed in intracellular and extracellular fluids. Protein inhibitors of enzymes other than proteinases are relatively rare. Such inhibitors are available for a-amylases, deoxyribonuclease I, phospholipase A, and protein kinases. 

Proteinase inhibitors (proteins) that circulate in plasma inactivate the hemostatic system proteinases after they have essentially completed their proteolyses. With two exceptions, o 2-niacroglobulin and tissue factor pathway inhibitor, all of the inhibitors of the procoagulant, anticoagulant, and fibrinolytic proteinases are SERPINS... 

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