There are four different C5 convertases able to specifically convert C5 glycoprotein (α-, β-chain) to C5a and C5b fragments. Two of them are physiological complement enzymes, associate to the cell-surface and mediate the classical pathway (C4b2a3b) or the alternative pathway (C3bBbC3b) of complement cascade. Two fluid phase C5 convertases have been described: the classical pathway enzyme, C4b2aoxy3b and the cobra venom factor-dependent C5 convertase, CVFBb.
The C5 convertases of the complement system are complex enzymes. In their most common forms the enzymes appear to be made up of a C3 convertase and an additional C3b or C4b molecule. The C3 convertases are themselves bimolecular complexes. In the classical pathway, the C3 convertase (C4b, C2a) consists of C2a, the proteolytic subunit, noncovalently bound to C4b. In the alternative pathway the C3 convertase has a similar structure with Bb, the proteolytic unit,noncovalently bound to a C3b molecule. Additional C3b molecules that are needed to allow efficient C5 cleavage by these C3 convertases are produced by the activation of C3 by the C3 convertases themselves (C4b, C2a, or C3b,Bb). The result of C3 activation is the covalent attachment of numerous C3b molecules within a few hundred angstroms of the C3 convertase. Originally it was thought that attachment of C3b molecules around the C3 convertase was sufficient to generate C5 convertase activity.
Vogt et al. revealed that the role of the additional C3b was to bind the substrate C5. Later a more defined structure was proposed in which the additional C3b binds covalently to a specific site on the C4b or C3b subunit of the C3 convertase resulting in the formation of the complexes C3b, C4b, C2a, or C3b2,Bb. These structures are now thought to be the functional C5 convertases of the classical and alternative pathways, respectively. However, other forms of the enzyme have been shown to be capable of activating C5. Cobra venom factor forms a C5 convertase (CVF,Bb) that contains no additional C3b and is not cell-bound. The fluid phase alternative pathway C3 convertase (C3b,Bb) has been reported to cleave C5 in the presence of additional free or cell-bound C3b. A covalent dimer of C4b that involves no C3b has been reported to express C5 convertase activity when complexed to C2a. A number of studies have examined the affinity of C5 for the non-enzymatic subunits C3b or C4b in the fluid phase or on surfaces. In contrast, by examining the Km of the enzyme we have measured the interaction of C5 with only those C3b molecules that are part of functional C5 convertases.
C5 convertases are serine proteases that cleave C5, the fifth component of complement. The cleavage of C5 is the last enzymatic step in the complement activation cascade resulting in the formation of two biologically important fragments, C5a and C5b. Both fragments play vital roles in killing microorganisms. C5a, the smaller fragment, is a potent chemotactic and spasmogenic anaphylatoxin. It mediates inflammatory responses by stimulating neutrophils and phagocytes. C5b, the larger fragment, initiates the formation of the membrane attack complex (C5b-9) which results in the lysis of bacteria and other pathogens. Although complement has important functions in host defense, it also contributes to the pathology in many inflammatory diseases, in xenotransplant rejection, and in reperfusion injury. This has prompted a search for inhibitors that can control activation of C5. Specific inhibition of C5 activation would preserve the immune clearance and opsonization functions of complement which depend on C3b, but it would prevent the generation of both C5a and C5b-9. Recent approaches in blocking complement activation include inhibitory anti-C5 antibodies, synthetic peptides, synthetic protease inhibitors, soluble constructs of complement membrane proteins, and transgenic animals that express proteins capable of inhibiting activation of human complement in xenotransplant models.
1. Cooper N R, et al. (1970). The reaction mechanism of human C5 in immune hemolysis. The Journal of experimental medicine, 132(4), 775-793.
2. DiScipio R G, et al. (1982). The activation of the alternative pathway C3 convertase by human plasma kallikrein. Immunology, 45(3), 587.
3. Medicus R G, et al. (1976). Alternative pathway of complement: recruitment of precursor properdin by the labile C3/C5 convertase and the potentiation of the pathway. The Journal of experimental medicine, 144(4), 1076-1093.