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A protease (also termed peptidase or proteinase) is any enzyme that conducts proteolysis, that is, begins protein catabolism by hydrolysis of the peptide bonds that link amino acids together in the polypeptide chain forming the protein.

Classification[link]

Standard[link]

Proteases are currently^[update] classified into six broad groups:

• Serine proteases
• Threonine proteases
• Cysteine proteases
• Aspartate proteases
• Metalloproteases
• Glutamic acid proteases

The threonine and glutamic-acid proteases were not described until 1995 and 2004, respectively. The mechanism used to cleave a peptide bond involves making an amino acid residue that has the cysteine and threonine (proteases) or a water molecule (aspartic acid, metallo- and glutamic acid proteases) nucleophilic so that it can attack the peptide carboxyl 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.

Within each of the broad groups proteases have been classified, by Rawlings and Barrett, into families of related proteases. For example within the serine proteases families are labelled Sx where S denotes the serine catalytic type and the x denotes the number of the family, for example S1 (chymotrypsins). An up to date classification of proteases into families is found in the MEROPS database.^[1][2]

By optimal pH[link]

Alternatively, proteases may be classified by the optimal pH in which they are active:

• Acid proteases
• Neutral proteases involved in type 1 hypersensitivity. Here, it is released by mast cells and causes activation of complement and kinins.^[3] This group includes the calpains.
• Basic proteases (or alkaline proteases)

Occurrence[link]

Proteases occur naturally in all organisms. 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). Proteases can either break 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 signaling pathway.

Bacteria also secrete proteases to hydrolyse (digest) the peptide bonds in proteins and therefore break the proteins down into their constituent monomers. Bacterial and fungal proteases are particularly important to the global carbon and nitrogen cycles in the recycling of proteins, and such activity tends to be regulated in by nutritional signals in these organisms.^[4] The net impact of nutritional regulation of protease activity among the thousands of species present in soil can be observed at the overall microbial community level as proteins are broken down in response to carbon, nitrogen, or sulfur limitation.^[5]

A secreted bacterial protease may also act as an exotoxin, and be an example of a virulence factor in bacterial pathogenesis. Bacterial exotoxic proteases destroy extracellular structures. Protease enzymes are also used extensively in the bread industry in bread improver.

Proteases, also known as proteinases or proteolytic enzymes, are a large group of enzymes. Proteases belong to the class of enzymes known as hydrolases, which catalyse the reaction of hydrolysis of various bonds with the participation of a water molecule.

Proteases are involved in digesting long protein chains into short fragments, splitting the peptide bonds that link amino acid residues. Some of them can detach the terminal amino acids from the protein chain (exopeptidases, such as aminopeptidases, carboxypeptidase A); the others attack internal peptide bonds of a protein (endopeptidases, such as trypsin, chymotrypsin, pepsin, papain, elastase).

Proteases are divided into four major groups according to the character of their catalytic active site and conditions of action: serine proteinases, cysteine (thiol) proteinases, aspartic proteinases, and metalloproteinases. Attachment of a protease to a certain group depends on the structure of catalytic site and the amino acid (as one of the constituents) essential for its activity.

Proteases are used throughout an organism for various metabolic processes. Acid proteases secreted into the stomach (such as pepsin) and serine proteases present in duodenum (trypsin and chymotrypsin) enable us to digest the protein in food; proteases present in blood serum (thrombin, plasmin, Hageman factor, etc.) play important role in blood-clotting, as well as lysis of the clots, and the correct action of the immune system. Other proteases are present in leukocytes (elastase, cathepsin G) and play several different roles in metabolic control. Proteases determine the lifetime of other proteins playing important physiological role like hormones, antibodies, or other enzymes—this is one of the fastest "switching on" and "switching off" regulatory mechanisms in the physiology of an organism. By complex cooperative action the proteases may proceed as cascade reactions, which result in rapid and efficient amplification of an organism's response to a physiological signal.

Proteases are part of many laundry detergents.

Inhibitors[link]

The activity of proteases is inhibited by protease inhibitors. One example of protease inhibitors is the serpin superfamily, which includes alpha 1-antitrypsin, C1-inhibitor, antithrombin, alpha 1-antichymotrypsin, plasminogen activator inhibitor-1, and neuroserpin.

Natural protease inhibitors include the family of lipocalin proteins, which play a role in cell regulation and differentiation. Lipophilic ligands, attached to lipocalin proteins, have been found to possess tumor protease inhibiting properties. The natural protease inhibitors are not to be confused with the protease inhibitors used in antiretroviral therapy. Some viruses, with HIV/AIDS among them, depend on proteases in their reproductive cycle. Thus, protease inhibitors are developed as antiviral means.

Degradation[link]

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 protease activity.

Protease research[link]

The field of protease research is enormous. Barrett and Rawlings estimated that approximately 8001 papers related to this field are published each year. For a look at current activities and interests of protease researchers, see the International Proteolysis Society web page.

See also[link]

• The Proteolysis Map
• TopFIND, a scientific database covering proteases, their cleavage site specificity, substrates, inhibitors and protein termini originating from their activity
• David Ho, an AIDS researcher famous for pioneering the use of protease inhibitors in treating HIV-infected patients
• Proteases in angiogenesis

Notes[link]

References[link]

External links[link]

• International Proteolysis Society
• Merops - the peptidase database
• List of protease inhibitors
• Protease cutting predictor
• List of proteases and their specificities (see also [1])
• Proteolysis MAP from Center for Proteolytic Pathways
• Proteolysis Cut Site database - curated expert annotation from users
• Protease cut sites graphical interface
• TopFIND protease database covering cut sites, substrates and protein termini
• Proteases at the US National Library of Medicine Medical Subject Headings (MeSH)