Convertase

So far, seven mammalian precursor convertases (PCs) have been identified furin, PCI, PC2, PC4, PC5, PACE4 and PC7. 

MMP-11 Stromelysin 3 Secreted MMP-11 shows more similarity to the MT-MMPs, is convertase-activatable and is secreted therefore usually associated to convertase-activatable MMPs. 

Like all neuropeptides, NT is synthesized as part of a larger precursor that also contains neuromedin N (NN), a 6 amino acid neurotensin-like peptide (Table 1). Pro-NT/NN is processed in the regulated secretory pathway of neuroendocrine cells by prohormone convertases PCI, PC2 and PC5-A that belong to a larger family of proprotein convertases. Due to differential cleavage specificity and tissue distribution of the convertases, pro-NT/NN processing gives rise to approximately a 1 1 and a 5 1 ratio of NT over NN content in the brain and gut, respectively. The peptides are stored in secretory vesicles and released from neuroendocrine cells in a Ca2+-dependent manner. NT and NN actions are terminated by desensitization of the... 

Proteins B, D and P also amplify the effects ofthe classical pathway in that some of the 3b generated by this pathway interacts with these proteins to form additional C3 convertase that supplements that provided by C4b.2a. Likewise, enhanced cleavage of C5 occurs due to the dual activity of C4.2a.3b and C3b.Bb.C3b complexes. 

C4BP C4 binding protein plasma protein which acts as co-factor to factor I inactivate C3 convertase C5a Complement fragment 5a (anaphylatoxin)... 

FIGURE 18-7 Processing of the proopiomelanocortin (POMC) precursor proceeds in an ordered, stepwise fashion. Cleavage of the POMC precursor occurs at seven sites, with some of the reactions being tissue-specific. The circled numbers indicate the temporal order of cleavage in tissues where these proteolytic events occur. ACTH, adrenocorticotropic hormone CLIP, corticotropin-like intermediate lobe peptide JP, joining peptide LPH, lipotropin MSH, melanocyte-stimulating hormone PC, prohormone convertase. 

Seidah, N. G. and Chretien, M. Proprotein and prohormone convertases a family of subtilases generating diverse bioactive polypeptides. Brain Res. 848 45-62,1999. 

Laurent, V., Jaubert-Miazza, L., Desjardins, R., Day, R. and Lindberg, I. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 145 519-528, 2004. 

Figure 1.15. Complement activation via the alternative pathway. Always present in serum are trace amounts of C3b, which may attach to recognition sites on, for example, yeast cell walls. C3b may combine with serum factor B to form C3bB, and this complex is acted upon by factor D to form C3bBb. This latter complex is a C3 convertase and may act upon C3 to form more C3b to amplify the process. The C3bBb-coated particles may activate other complement components (C4-C9) or be recognised by complement receptors on neutrophils.

SB 1 Family of endo- and exopeptidases (including proprotein convertases) Asp, His, Ser Parallel /3-sheet... 

Some medicines, such as non-steroid anti-inflammatory drugs, convertase inhibitors, and (3-blockers, may intensify food allergy symptoms (Brooks et ah, 1989 Meune et ah, 2000 Tenenbaum et ah, 2000). 

Any one of these pathways, or all three, result in proteolytic cleavage of a protein known as C3 convertase to produce the active form, C3b. The latter is involved in different mechanisms that kill bacteria (Figure 17.7). 

Figure 17.24 Activation of C3 convertase and effects of activation. There are three pathways that activate complement and four mechanisms that facilitate the killing of pathogens (see text). C3 is the convertase enzyme.

Complement Some microorganisms produce proteins that bind to and inactivate components of the complement system and hence decrease activation of the cascade, e.g. the vaccinia virus secretes a protein that inhibits activation of both the classical and alternative pathways. Some bacteria produce a protein that mimics the action of an acceleration factor, which increases the rate of destruction of the active convertase this factor is normally produced by the host when the complement response is no longer required. 

The classic pathway is triggered by the formation of factor Cl at IgG or IgM on the surface of microorganisms (left). Cl is an 18-part molecular complex with three different components (Clq, Clr, and Cls). Clq is shaped like a bunch of tulips, the flowers of which bind to the Fc region of antibodies (left). This activates Clr, a serine proteinase that initiates the cascade of the classic pathway. First, C4 is proteolytically activated into C4b, which in turn cleaves C2 into C2a and C2b. C4B and C2a together form C3 convertase [1], which finally catalyzes the cleavage of C3 into C3a and C3b. Small amounts of C3b also arise from non-enzymatic hydrolysis of C3. 

The alternative pathway starts with the binding of factors C3b and B to bacterial lipo-polysaccharides (endotoxins). The formation of this complex allows cleavage of B by factor D, giving rise to a second form of C3 convertase (C3bBb). 

The late factors C5 to C9 are responsible for the development of the membrane attack complex (bottom). They create an ion-permeable pore in the bacterial membrane, which leads to lysis of the pathogen. This reaction is triggered by C5 convertase [2]. Depending on the type of complement activation, this enzyme has the structure C4b2o3b or C3bBb3b, and it cleaves C5 into C5a and C5b. The complex of C5b and C6 allows deposition of C7 in the bacterial membrane. C8 and numerous C9 molecules—which form the actual pore—then bind to this core. 

---