Activation of proteases via the cysteine switch

There are a number of potential ways by which ROIs released from inflammatory cells may also indirectly effect structure and function of connective tissue. Oxidants may compromise connective tissue integrity through the activation of proteinases secreted in latent form (i.e. as zymogens) (see Fig. 2). 

Latent forms of MMPs can be activated by mechanisms which cause the dissociation of the intramolecular complex between a particular cysteine residue and the required zinc metal ligand (a complex that blocks the active site) [47], This occurs because the cysteine of the latent enzyme is coordinated to the active site in a particular way that blocks the MMP active site. Collectively, the activation of MMPs occurs through a process which has been termed the cysteine-switch . Activators of the MMPs include proteases (e.g. plasmin), conformational perturbants (SDS, NaSCN), heavy metals and organomercurials (e.g. Au(I) compounds, Hg(II)), oxidants (e.g. OC1-), disulfide compounds (e.g. GSSG) and sulfhydryl alkylating agents (e.g. V-ethylmaleimide) [47 and refs, therein]. 

Although the favoured candidate for physiological activation of MMPs is through the classical zymogen activation by proteolysis, oxidative activation may be critical under certain pathological conditions (e.g., specifically at inflammatory foci) (see Fig. 2). Since there is considerable variation in the ability of proteinases to activate MMPs, the oxidative route may be more 

Active site amino acid sequence of selected serine protease inhibitors (serpins) and their sensitivity 

Serpin3 Active site amino acid sequence11 Oxidant sensitivity 

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