Complement C3 convertase, C5 convertase, and membrane attack complex (C3 convertase, C5 convertase, and MAC)

Complement C3 convertase and C5 convertase are multi-subunit serine protease complexes that drive the central amplification and terminal effector steps of the complement cascade, respectively, culminating in formation of the membrane attack complex (MAC). In the classical/lectin pathway, C3 convertase is C4b2a and C5 convertase is C4b2a3b; in the alternative pathway, C3 convertase is C3bBb and the C5 convertase is a C3b-enriched form, commonly denoted C3bBb(C3b)n.[2][3][4] C5 convertase cleaves C5 into the anaphylatoxin C5a and C5b; C5b sequentially recruits C6, C7, C8, and multiple C9 molecules to assemble the MAC (C5b-9), a β-barrel pore that inserts into membranes and can lyse target cells.[1][2][6] Local, in situ generation of C5b by surface-bound C5 convertase is critical for efficient, bactericidal MAC insertion into bacterial membranes; preassembled C5b-6 complexes lack robust bactericidal activity unless formed at the surface by convertases.[5] MAC assembly proceeds via C5b6 binding C7 to anchor to membranes, recruitment of C8 to form C5b-8 with initial insertion, and polymerization of approximately 10–18 C9 subunits to complete the pore; human CD59 restricts MAC by preventing C9 polymerization.[1][2][6] Because convertases generate C3a/C3b and C5a/C5b—the mediators of opsonization, chemotaxis, inflammation, and terminal lysis—they are validated therapeutic targets; drugs that inhibit C5 or C3 reduce inflammation and prevent MAC-mediated tissue injury across complement-driven diseases.[1][3][6]

Other names

C3/C5 convertasesTerminal complement complexC5b-9 complexComplement terminal pathwayClassical pathway C3 convertase (C4b2a)Classical pathway C5 convertase (C4b2a3b)Alternative pathway C3 convertase (C3bBb)Alternative pathway C5 convertase [C3bBb(C3b)n]Membrane attack complex (MAC)Terminal complement complex (TCC)

Inhibition of C5 cleavage to block C5a generation and MAC formation (anti-C5 antibodies; C5 inhibitors)[1][2][5][6] Inhibition of C3 activation to reduce C3b opsonization and prevent assembly of C3/C5 convertases and downstream MAC (C3 inhibitors)[3] Blockade of classical/lectin pathway proteases to prevent formation of C3/C5 convertases (anti-C1s, anti-MASP-2)[3][4] Selective inhibition of C5 convertases by targeting the C3b thioester domain (TED) to disrupt accessory C3b needed for C5 conversion (e.g., Efb-C/Ecb, FHR5 experimental inhibitors)[3]