Some proteins and most eukaryotic polypeptide hormones are synthesized as a large precursor polypeptide known as polyprotein that require proteolytic cleavage into individual smaller polypeptide chains. The polyprotein pro-opiomelanocortin (POMC) contains many polypeptide hormones. The cleavage pattern of POMC, however, may vary between different tissues, yielding different sets of polypeptide hormones from the same polyprotein.
Many viruses also produce their proteins initially as a single polypeptide chain that were translated from a polycistronic mRNA. This polypeptide is subsequently cleaved into individual polypeptide chains.
Many proteins and hormones are synthesized in the form of their precursors - zymogens, proenzymes, and prehormones. These proteins are cleaved to form their final active structures. Insulin, for example, is synthesized as preproinsulin, which yields proinsulin after the signal peptide has been cleaved. To form the mature insulin, the proinsulin is then cleaved at two positions to yield two polypeptide chains linked by 2 disulphide bonds. Proinsulin is necessary for the folding of the polypeptide chain, as the 2 polypeptide chains of insulin may not correctly assemble into the correct form, whereas its precursor proinsulin does.
Proteases in particular are synthesized in the inactive form so that they may be safely stored in cells, and ready for release in sufficient quantity when required. This is to ensure that the protease is activated only in the correct location or context, as inappropriate activation of these proteases can be very destructive for an organism. Proteolysis of the zymogen yields an active protein; for example, when trypsinogen is cleaved to form trypsin, a slight rearrangement of the protein structure that completes the active site of the protease occurs, thereby activating the protein.
Proteolysis can, therefore, be a method of regulating biological processes by turning inactive proteins into active ones. A good example is the blood clotting cascade whereby an initial event triggers a cascade of sequential proteolytic activation of many specific proteases, resulting in blood coagulation. The complement system of the immune response also involves a complex sequential proteolytic activation and interaction that result in an attack on invading pathogens.
Proteolytic cleavage breaks down proteins in food extracellularly into smaller peptides and amino acids so that they may be absorbed and used by an organism. Proteins in cells are also constantly being broken down into amino acids. This intracellular degradation of protein serves a number of functions: It removes damaged and abnormal protein and prevent their accumulation, and it also serves to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed.然后，氨基酸可再次被用于蛋白质合成。
The intracellular degradation of protein may be achieved in two ways - proteolysis in lysosome, or a ubiquitin-dependent process that targets unwanted proteins to proteasome. The autophagy-lysosomal pathway is normally a non-selective process, but it may become selective upon starvation whereby proteins with peptide sequence KFERQ or similar are selectively broken down. The lysosome contains a large number of proteases such as cathepsins.
The ubiquitin-mediated process is selective. Proteins marked for degradation are covalently linked to ubiquitin. Many molecules of ubiquitin may be linked in tandem to a protein destined for degradation. The polyubiquinated protein is targeted to an ATP-dependent protease complex, the proteasome. The ubiquitin is released and reused, while the targeted protein is degraded.
Different proteins are degraded at different rate. Abnormal proteins are quickly degraded, whereas the rate of degradation of normal proteins may vary widely depending on their functions. Enzymes at important metabolic control points may be degraded much faster than those enzymes whose activity is largely constant under all physiological conditions. One of the most rapidly degraded proteins is ornithine decarboxylase, which has a half-life of 11 minutes. In contrast, other proteins like actin and myosin have half-life of a month or more, while, in essence, haemoglobin lasts for the entire life-time of erythrocyte.
The N-end rule may partially determine the half-life of a protein, and proteins with segments rich in proline, glutamic acid, serine, and threonine (the so-called PEST proteins) have short half-life. Other factors suspected to affect degradation rate include the rate deamination of glutamine and asparagine and oxidation of cystein, histidine, and methionine, the absence of stabilizing ligands, the presence of attached carbohydrate or phosphate groups, the presence of free α-amino group, the negative charge of protein, and the flexibility and stability of the protein.
The rate of proteolysis may also depend on the physiological state of the cell, such as its hormonal state as well as nutritional status. In time of starvation, the rate of protein degradation increases.
In human digestion, proteins in food are broken down into smaller peptide chains by digestive enzymes such as pepsin, trypsin, chymotrypsin, and elastase, and into amino acids by various enzymes such as carboxypeptidase, aminopeptidase, and dipeptidase. It is necessary to break down proteins into small peptides (tripeptides and dipeptides) and amino acids so they can be absorbed by the intestines, and the absorbed tripeptides and dipeptides are also further broken into amino acids intracellularly before they enter the bloodstream. Different enzymes have different specificity for their substrate; trypsin, for example, cleaves the peptide bond after a positively charged residue (arginine and lysine); chymotrypsin cleaves the bond after an aromatic residue (phenylalanine, tyrosine, and tryptophan); elastase cleaves the bond after a small non-polar residue such as alanine or glycine.
In order to prevent inappropriate or premature activation of the digestive enzymes (they may, for example, trigger pancreatic self-digestion causing pancreatitis), these enzymes are secreted as inactive zymogen. The precursor of pepsin, pepsinogen, is secreted by the stomach, and is activated only in the acidic environment found in stomach. The pancreas secretes the precursors of a number of proteases, such as trypsin and chymotrypsin. The zymogen of trypsin is trypsinogen, which is activated by a very specific protease, enterokinase, secreted by the mucosa of the duodenum. The trypsin, once activated, can also cleave other trypsinogens as well as the precursors of other proteases such as chymotrypsin and carboxypeptidase.
In bacteria, a similar strategy of employing an inactive zymogen or prezymogen is used. Subtilisin, which is produced by Bacillus subtilis, is produced as preprosubtilisin, and is released only if the signal peptide is cleaved and autocatalytic proteolytic activation has occurred.
- ^ 1.0 1.1 Thomas E Creighton. Proteins: Structures and Molecular Properties 2nd. W H Freeman and Company. 1993: 78–86. ISBN 0-7167-2317-4.
- ^ P H Hirel, M J Schmitter, P Dessen, G Fayat, and S Blanquet. Extent of N-terminal methionine excision from Escherichia coli proteins is governed by the side-chain length of the penultimate amino acid. Proc Natl Acad Sci U S A. 1989, 86 (21): 8247–51. doi:10.1073/pnas.86.21.8247. PMC 298257. PMID 2682640.
- ^ 3.0 3.1 Thomas E Creighton. Chapter 10 - Degradation//Proteins: Structures and Molecular Properties 2nd. W H Freeman and Company. 1993: 463–473. ISBN 0-7167-2317-4.
- ^ Voet & Voet. Biochemisty 2nd. John Wiley & Sons. 1995: 1010–1014. ISBN 0-471-58651-X.
- ^ Silk DB. Progress report. Peptide absorption in man. Gut. 1974, 15 (6): 494–501. doi:10.1136/gut.15.6.494. PMC 1413009. PMID 4604970.