Pro-protein

A small number of proteins, and again insulin is an example, are synthesized as pro-proteins with an additional amino acid sequence which dictates the final three-dimensional structure. In the case of proinsulin, proteolytic attack cleaves out a stretch of 35 amino acids in the middle of the molecule to generate insulin. The peptide that is removed is known as the C chain. The other chains, A and B, remain crosslinked and thus locked in a stable tertiary stiucture by the disulphide bridges formed when the molecule originally folded as proinsulin. Bacteria have no mechanism for specifically cutting out the folding sequences from pro-hormones and the way of solving this problem is described in a later section. 

Cytokines are peptides that are produced and secreted by cells of the immune system. They organise the immune response to invasion by a pathogen by communicating between the different cells. They are synthesised in the immune cells as precursor proteins (pro-proteins) from which a peptide is removed by a proteolytic enzyme to produce the active cytokine, prior to secretion. This enzyme is a serine protease. Perhaps surprisingly, some viruses are capable of synthesising serpins which inhibit this enzyme in the immune cells, so that secretion does not occur and communication and integration of the immune response to the viral infection is lost. This is one of many biochemical mechanisms by which pathogens can reduce or overcome the defence mechanisms of the host (Chapter 17). 

The nasal route is generating increasing interest as a route for the administration of local treatments and a cost-effective and patient-friendly alternative to injection for systemic delivery [49]. The special advantages of nasal delivery make it attractive for (i) crisis treatment where rapid onset of action is desirable (e.g., pain, migraine, panic attacks), (ii) systemic delivery of compounds that at present can only be delivered by injection (peptides/pro-proteins/vaccination), and (iii) direct targeting of the CNS (polar drugs for the treatment of CNS disorders). 

APP cleavage to occur (Shi et al., 2001), and removal is carried out by furin, a member of the pro-protein convertase enzymes (Bennett et al., 2000). Furin is a calcium dependent protease and so increases in calcium lead to an increase in activity. Treatment of cells with a calcium ionophore (A23187), which depleted intracellular stores of calcium, leads to a reduction in both furin and BACE activity (Bennett et al., 2000) and thus demonstrates one pathway through how intracellular calcium can regulate A 3 production through BACE. 

However the synthesis of the polypeptide (typically a precursor pro-protein) is followed by various processes that can include targeting of polypeptides to specific organelles (e.g. mitochondria, ER, nucleus, vacuole or indeed for extracellular export), assistance with protein folding to form the proper tertiary structure, proteolytic processing (removing parts of the pro-protein) and further covalent modification (notably by glycosylation). Protein... 

Proteins are typically made as pro-proteins and are then subsequently modified by post-translational processing involving selective proteolysis ( trimming ) and addition of other groups. Thus, nascent polypeptides commence with N-formylmethionine (bacteria) or methionine (eukaryotes). However, N-terminal sequences are often removed in proteolytic processing. In many eukaryote proteins, the final N-terminal amino acid of the processed protein is N-acetylated. The C-terminus may also be changed by peptide cleavage and other covalent modification. 

Fragaria OLP (24 kDa pro-protein) Lycopersicon OLP (27 kDa pro-protein) Mcotiana sylvestris OLPs (28 kDa pro-proteins) Mcotiana tabacum Osmotin OLPs (28 kDa pro-proteins)... 

All human metzincins are secreted as proenzymes. Astacins and adamalysins are mostly activated by calcium-ion-dependent serine proteases pro-protein convertases) that meet up with their substrates in trans-Golgi and secretory vacuoles. These proenzymes are known as furin-like convertases because of their homology to a serine protease called furin and a bacterial endoprotease called subtilisin. The furin-like enzymes require calcium ions to maintain structural stability whereas other serine proteases, represented by trypsin and chymotrypsin, do not. The furin-like pro-protein convertases autocleave their own N-terminal domain propeptide (self-activate) during secretion and then convert the N-terminal domains of co-secreted metzincins. Activation cascades also occur among the... 

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