Protease

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Proteases (proteinases, peptidases or proteolytic enzymes) are enzymes that break peptide bonds between amino acids of proteins. The process is called proteolytic cleavage, a common mechanism of activation or inactivation of enzymes especially involved in blood coagulation or digestion. They use a molecule of water for this and are thus classified as hydrolases.

1 Classification
2 Occurrence
3 Inhibitors
4 Degradation
5 Protease research
6 References
7 External links

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Classification

There are currently six classes of proteases:

Serine proteases
Threonine proteases
Cysteine proteases
Aspartic acid proteases (e. g. plasmepsin)
Metalloproteases
Glutamic acid proteases

The threonine and glutamic peptidases were not described until 1995 and 2004, respectively. The mechanism used to cleave a peptide bond involves making an amino acid residue (serine, cystein and threonine peptidases) or a water molecule (aspartic, metallo and glutamic peptidases) nucleophilic so that it can attack the peptide carbonyl group. One way to make a nucleophile is by a catalytic triad, where a histidine residue is used to activate serine, cysteine or threonine as a nucleophile.

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Occurrence

Proteases occur naturally in all organisms and constitute 1-5% of the gene content. These enzymes are involved in a multitude of physiological reactions from simple digestion of food proteins to highly regulated cascades (e.g. the blood clotting cascade, the complement system, apoptosis pathways, and the invertebrate prophenoloxidase activating cascade). Peptidases can break either specific peptide bonds (limited proteolysis), depending on the amino acid sequence of a protein, or break down a complete peptide to amino acids (unlimited proteolysis). The activity can be a destructive change abolishing a protein's function or digesting it to its principal components, it can be an activation of a function or it can be a signal in a signalling pathway.

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Inhibitors

The function of peptidases is inhibited by protease inhibitor enzymes. Examples of protease inhibitors are the class of serpins (serine protease or peptidase inhibitors), incorporating alpha 1-antitrypsin. Other serpins are complement 1-inhibitor, antithrombin, alpha 1-antichymotrypsin, plasminogen activator inhibitor 1 (coagulation, fibrinolysis) and the recently discovered neuroserpin.

The natural protease inhibitors are not to be confused with the protease inhibitors used in antiretroviral therapy. Some viruses, with HIV among them, depend on proteases in their reproductive cycle. Thus, protease inhibitors are developed as antiviral means.

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Degradation

Proteases, being themselves proteins, are known to be cleaved by other protease molecules, sometimes of the same variety. This may be an important method of regulation of peptidase activity.

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Protease research

The field of protease research is enormous. Barrett and Rawlings estimated that approximately 8000 papers related to this field are published each year.

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References

Barrett AJ, Rawlings ND, Woessner JF. The Handbook of Proteolytic Enzymes, 2nd ed. Academic Press, 2003. ISBN 0120796104.
Hedstrom L. Serine Protease Mechanism and Specificity. Chem Rev 2002;102:4501-4523.
Southan C. A genomic perspective on human proteases as drug targets. Drug Discov Today 2001;6:681-688.
Hooper NM. Proteases in Biology and Medicine. London: Portland Press, 2002. ISBN 1855781476.
Puente XS, Sanchez LM, Overall CM, Lopez-Otin C. Human and Mouse Proteases: a Comparative Genomic Approach. Nat Rev Genet 2003;4:544-558.
Ross J, Jiang H, Kanost MR, Wang Y. Serine proteases and their homologs in the Drosophila melanogaster genome: an initial analysis of sequence conservation and phylogenetic relationships. Gene 2003;304:117-31.
Puente XS, Lopez-Otin C. A Genomic Analysis of Rat Proteases and Protease Inhibitors. Genome Biol 2004;14:609-622.