Editing Proteolysis (section)

===Protein degradation===
Protein degradation may take place intracellularly or extracellularly. In digestion of food, digestive enzymes may be released into the environment for [[extracellular digestion]] whereby proteolytic cleavage breaks proteins into smaller peptides and amino acids so that they may be absorbed and used. In animals the food may be processed extracellularly in specialized [[digestive tract|organs]] or [[Gut (anatomy)|gut]]s, but in many bacteria the food may be internalized via [[phagocytosis]]. Microbial degradation of protein in the environment can be regulated by nutrient availability. For example, limitation for major elements in proteins (carbon, nitrogen, and sulfur) induces proteolytic activity in the fungus ''[[Neurospora crassa]]''<ref>Hanson, M.A., Marzluf, G.A., 1975. Control of the synthesis of a single enzyme by multiple regulatory circuits in Neurospora crassa. Proc. Natl. Acad. Sci. U.S.A. 72, 1240–1244.</ref> as well as in of soil organism communities.<ref>Sims, G. K., and M. M. Wander. 2002. Proteolytic activity under nitrogen or sulfur limitation. Appl. Soil Ecol. 568:1-5.</ref>

Proteins in cells are broken into amino acids. This intracellular degradation of protein serves multiple functions: It removes damaged and abnormal proteins and prevents their accumulation. It also serves to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed. The amino acids may then be reused for protein synthesis.

====Lysosome and proteasome====
[[File:Proteaosome 1fnt side.png|thumb|upright=0.6|Structure of a proteasome. Its active sites are inside the tube (blue) where proteins are degraded.]]

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.

====Rate of intracellular protein degradation====
Different proteins are degraded at different rates. 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 a half-life of a month or more, while, in essence, [[haemoglobin]] lasts for the entire life-time of an [[erythrocyte]].<ref name="degradation">{{cite book |author=Thomas E Creighton |title=Proteins: Structures and Molecular Properties |edition=2nd |chapter=Chapter 10 - Degradation |pages=[https://archive.org/details/proteinsstructur0000crei/page/463 463–473] |year=1993 |publisher=W H Freeman and Company |isbn=978-0-7167-2317-2 |chapter-url=https://archive.org/details/proteinsstructur0000crei |url=https://archive.org/details/proteinsstructur0000crei/page/463 }}</ref>

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 sequence|PEST protein]]s) have short half-life.<ref>{{cite book |author=Voet & Voet |title=Biochemistry |pages=[https://archive.org/details/biochemistry00voet_0/page/1010 1010–1014] |edition=2nd |year=1995 |publisher=John Wiley & Sons |isbn=978-0-471-58651-7 |url=https://archive.org/details/biochemistry00voet_0/page/1010 }}</ref> 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.<ref name="degradation"/> Proteins with larger degrees of [[Intrinsically disordered proteins|intrinsic disorder]] also tend to have short cellular half-life,<ref>{{Cite journal|title = Structural disorder serves as a weak signal for intracellular protein degradation|journal = Proteins|date = 2008-05-01|issn = 1097-0134|pmid = 18004785|pages = 903–909|volume = 71|issue = 2|doi = 10.1002/prot.21773|first1 = P.|last1 = Tompa|first2 = J.|last2 = Prilusky|first3 = I.|last3 = Silman|first4 = J. L.|last4 = Sussman|s2cid = 13942948}}</ref> with disordered segments having been proposed to facilitate efficient initiation of degradation by the [[proteasome]].<ref>{{Cite journal|title = Paradigms of protein degradation by the proteasome|journal = Current Opinion in Structural Biology|date = 2014-02-01|issn = 1879-033X|pmc = 4010099|pmid = 24632559|pages = 156–164|volume = 24|doi = 10.1016/j.sbi.2014.02.002|first1 = Tomonao|last1 = Inobe|first2 = Andreas|last2 = Matouschek}}</ref><ref>{{Cite journal|title = Intrinsically Disordered Segments Affect Protein Half-Life in the Cell and during Evolution|journal = Cell Reports| date=25 September 2014| issn = 2211-1247|pmc = 4358326|pmid = 25220455|pages = 1832–1844|volume = 8|issue = 6| doi = 10.1016/j.celrep.2014.07.055|first1 = Robin|last1 = van der Lee|first2 = Benjamin|last2 = Lang|first3 = Kai|last3 = Kruse|first4 = Jörg|last4 = Gsponer|first5 = Natalia|last5 = Sánchez de Groot|first6 = Martijn A.|last6 = Huynen|first7 = Andreas|last7 = Matouschek|first8 = Monika|last8 = Fuxreiter|first9 = M. Madan|last9 = Babu}}</ref> 
 
The rate of proteolysis may also depend on the physiological state of the organism, such as its hormonal state as well as nutritional status. In time of starvation, the rate of protein degradation increases.

====Digestion====
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.<ref>{{cite journal |author=Silk DB |title=Progress report. Peptide absorption in man|journal=Gut |volume=15|issue=6|pages=494–501|year=1974|pmid= 4604970 |pmc=1413009 |doi=10.1136/gut.15.6.494 }}</ref> 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 to activate them.

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.