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A protease (also called a peptidase or proteinase) is an
enzyme Enzymes () are s that act as s (biocatalysts). Catalysts accelerate . The molecules upon which enzymes may act are called , and the enzyme converts the substrates into different molecules known as . Almost all in the need in order to occu ...

enzyme
that
catalyzes that utilizes a low-temperature oxidation catalyst to convert carbon monoxide to less toxic carbon dioxide Carbon dioxide (chemical formula ) is a colorless gas with a density about 53% higher than that of dry air. Carbon dioxide molecules ...

catalyzes
(increases
reaction rate has a ''low'' reaction rate. This process is slow. The reaction rate or rate of reaction is the speed at which a chemical reaction A chemical reaction is a process that leads to the IUPAC nomenclature for organic transformations, chemical trans ...
or "speeds up")
proteolysis Proteolysis is the breakdown of protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, incl ...

proteolysis
, breaking down
proteins Proteins are large biomolecule , showing alpha helices, represented by ribbons. This poten was the first to have its suckture solved by X-ray crystallography by Max Perutz and Sir John Cowdery Kendrew in 1958, for which they received a Nobe ...

proteins
into smaller
polypeptide Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēnikḗ'') is an independent branch of the Indo-European languages, Indo-European family of languages, native to Greece, Cyprus, Albania, o ...
s or single
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
s, and spurring the formation of new protein products. They do this by cleaving the
peptide bonds In organic chemistry Organic chemistry is a branch of chemistry that studies the structure, properties and reactions of organic compounds, which contain carbon in covalent bonding.Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistr ...
within proteins by
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution Substitution may refer to: Arts and media *Chord substitution, in music, swapping one chord for ...

hydrolysis
, a reaction where
water Water (chemical formula H2O) is an , transparent, tasteless, odorless, and , which is the main constituent of 's and the s of all known living organisms (in which it acts as a ). It is vital for all known forms of , even though it provide ...

water
breaks bonds. Proteases are involved in many biological functions, including
digestion Digestion is the breakdown of large insoluble food Food is any substance consumed to provide Nutrient, nutritional support for an organism. Food is usually of plant, animal or Fungus, fungal origin, and contains essential nutrients, such as ...
of ingested proteins, protein catabolism (breakdown of old proteins), and
cell signaling In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processes, Molecular biology, molecular interactions, Physiology, physiological mechanisms, ...
. In the absence of functional accelerants, proteolysis would be very slow, taking hundreds of
years A year is the orbital period of a planetary body, for example, the Earth, moving in its orbit around the Sun. Due to the Earth's axial tilt, the course of a year sees the passing of the season A season is a division of the year based on ...
. Proteases can be found in all forms of life and
virus A virus is a that only inside the living of an . Viruses infect all , from animals and plants to s, including and . Since 's 1892 article describing a non-bacterial infecting tobacco plants and the discovery of the by in 1898, more ...

virus
es. They have independently evolved multiple times, and different classes of protease can perform the same reaction by completely different
catalytic mechanism Enzyme catalysis is the increase in the rate of a process by a Biomolecule, biological molecule, an "enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized s ...
s.


Hierarchy of proteases


Based on catalytic residue

Proteases can be classified into seven broad groups: *
Serine protease Serine proteases (or serine endopeptidases) are s that cleave s in s. serves as the at the (enzyme's) . They are found ubiquitously in both and . Serine proteases fall into two broad categories based on their structure: -like (trypsin-l ...

Serine protease
s - using a
serine Serine (symbol Ser or S) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

serine
alcohol In , alcohol is an that carries at least one (−OH) bound to a atom. The term alcohol originally referred to the primary alcohol (ethyl alcohol), which is and is the main alcohol present in s. An important class of alcohols, of which ...

alcohol
*
Cysteine protease Cysteine proteases, also known as thiol proteases, are enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chem ...
s - using a
cysteine Cysteine (symbol Cys or C; ) is a semi essential proteinogenic amino acid with the formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions, as a nucleophile. The thiol is susceptible to oxida ...

cysteine
thiol A thiol () or thiol derivative is any organosulfur compound Organosulfur compounds are organic compounds that contain sulfur. They are often associated with foul odors, but many of the sweetest compounds known are organosulfur derivatives, e.g., sa ...

thiol
*
Threonine protease Threonine proteases are a family of proteolytic enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry ...
s - using a
threonine Threonine (symbol Thr or T) is an amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with a Substituent, side chain (R group) specific to each amino acid. ...

threonine
secondary alcohol upright=0.8, The bond angle between a hydroxyl group (-OH) and a chain of carbon atoms (R) In chemistry Chemistry is the scientific discipline involved with Chemical element, elements and chemical compound, compounds composed of atoms, ...

secondary alcohol
*
Aspartic protease Aspartic proteases are a catalytic type of protease A protease (also called a peptidase or proteinase) is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecul ...

Aspartic protease
s - using an aspartate
carboxylic acid A carboxylic acid is an organic acid An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acid ...
*
Glutamic protease Glutamic proteases are a group of proteolytic enzymes containing a glutamic acid residue within the active site. This type of protease was first described in 2004 and became the sixth catalytic type of protease. Members of this group of protease had ...

Glutamic protease
s - using a
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with a Substituent, sid ...
carboxylic acid A carboxylic acid is an organic acid An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acid ...
*
Metalloprotease A metalloproteinase, or metalloprotease, is any protease A protease (also called a peptidase or proteinase) is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The m ...
s - using a
metal A metal (from Greek Greek may refer to: Greece Anything of, from, or related to Greece Greece ( el, Ελλάδα, , ), officially the Hellenic Republic, is a country located in Southeast Europe. Its population is approximately 10.7 mi ...

metal
, usually
zinc Zinc is a chemical element Image:Simple Periodic Table Chart-blocks.svg, 400px, Periodic table, The periodic table of the chemical elements In chemistry, an element is a pure substance consisting only of atoms that all have the same numbe ...

zinc
*
Asparagine peptide lyases Asparagine (symbol Asn or N), is an α-amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with a Substituent, side chain (R group) specific to each amino ...
- using an
asparagine Asparagine (symbol Asn or N), is an α-amino acid that is Proteinogenic amino acid, used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), an α-carboxylic acid gr ...

asparagine
to perform an
elimination reaction Image:EliminationReactionCyclohexene.svg, frame, Elimination reaction of cyclohexanol to cyclohexene with sulfuric acid and heat An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a ...

elimination reaction
(not requiring water) Proteases were first grouped into 84 families according to their evolutionary relationship in 1993, and classified under four catalytic types: serine, cysteine, aspartic, and metallo proteases. The
threonine Threonine (symbol Thr or T) is an amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with a Substituent, side chain (R group) specific to each amino acid. ...

threonine
and glutamic-acid proteases were not described until 1995 and 2004 respectively. The mechanism used to cleave a
peptide bond In organic chemistry, a peptide bond is an amide type of Covalent bond, covalent chemical bond linking two consecutive alpha-amino acids from C1 (carbon number one) of one alpha-amino acid and N2 (nitrogen number two) of another, along a peptide o ...

peptide bond
involves making an
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
residue that has the
cysteine Cysteine (symbol Cys or C; ) is a semi essential proteinogenic amino acid with the formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions, as a nucleophile. The thiol is susceptible to oxida ...

cysteine
and threonine (proteases) or a water molecule ( aspartic acid, metallo- and acid proteases) nucleophilic so that it can attack the peptide
carboxyl A carboxylic acid is an organic acid that contains a carboxyl group (C(=O)OH) attached to an R-group. The general formula of a carboxylic acid is R−COOH or R−CO2H, with substituent, R referring to the alkyl, alkenyl, aryl, or other group. ...

carboxyl
group. One way to make a nucleophile is by a
catalytic triad A catalytic triad is a set of three coordinated amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen ...

catalytic triad
, where a
histidine Histidine (symbol His or H) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond ...

histidine
residue is used to activate
serine Serine (symbol Ser or S) is an α-amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, ...

serine
,
cysteine Cysteine (symbol Cys or C; ) is a semi essential proteinogenic amino acid with the formula HOOC-CH-(NH2)-CH2-SH. The thiol side chain in cysteine often participates in enzymatic reactions, as a nucleophile. The thiol is susceptible to oxida ...

cysteine
, or
threonine Threonine (symbol Thr or T) is an amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with a Substituent, side chain (R group) specific to each amino acid. ...

threonine
as a nucleophile. This is not an evolutionary grouping, however, as the nucleophile types have in different superfamilies, and some superfamilies show divergent evolution to multiple different nucleophiles.


Peptide lyases

A seventh catalytic type of proteolytic enzymes, asparagine peptide lyase, was described in 2011. Its proteolytic mechanism is unusual since, rather than
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution Substitution may refer to: Arts and media *Chord substitution, in music, swapping one chord for ...

hydrolysis
, it performs an
elimination reaction Image:EliminationReactionCyclohexene.svg, frame, Elimination reaction of cyclohexanol to cyclohexene with sulfuric acid and heat An elimination reaction is a type of organic reaction in which two substituents are removed from a molecule in either a ...

elimination reaction
. During this reaction, the catalytic asparagine forms a cyclic chemical structure that cleaves itself at asparagine residues in proteins under the right conditions. Given its fundamentally different mechanism, its inclusion as a peptidase may be debatable.


Evolutionary phylogeny

An up-to-date classification of protease evolutionary superfamilies is found in the MEROPS database. In this database, proteases are classified firstly by 'clan' (
superfamily SUPERFAMILY is a database and search platform of structural and functional annotation for all proteins and genomes. It classifies amino acid sequences into known structural domains, especially into SCOP superfamilies. Domains are functional, str ...
) based on structure, mechanism and catalytic residue order (e.g. the
PA clan The PA clan (protease, Proteases of mixed nucleophile, Protein superfamily, superfamily A) is the largest group of proteases with common ancestry as identified by structural homology. Members have a chymotrypsin-like fold and similar proteolysis me ...
where P indicates a mixture of nucleophile families). Within each 'clan', proteases are classified into
families In human society, family (from la, familia) is a Social group, group of people related either by consanguinity (by recognized birth) or Affinity (law), affinity (by marriage or other relationship). The purpose of families is to maintain the w ...
based on sequence similarity (e.g. the S1 and C3 families within the PA clan). Each family may contain many hundreds of related proteases (e.g.
trypsinTrypsin () is a serine protease of Trypsin, a typical serine protease. Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. ...
,
elastase 200px, Crystals of porcine elastase. In molecular biology, elastase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are ...

elastase
,
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma-t ...
and streptogrisin within the S1 family). Currently more than 50 clans are known, each indicating an independent evolutionary origin of proteolysis.


Classification based on optimal pH

Alternatively, proteases may be classified by the optimal in which they are active: *''Acid proteases'' *''Neutral proteases'' involved in
type 1 hypersensitivity Type I hypersensitivity (or immediate hypersensitivity) is an allergic reaction provoked by re-exposure to a specific type of antigen In immunology, an antigen (Ag) is a molecule or molecular structure, such as may be present on the outside of ...
. Here, it is released by
mast cell#REDIRECT Mast cell A mast cell (also known as a mastocyte or a labrocyte) is a resident cell of connective tissue that contains many granules rich in histamine and heparin. Specifically, it is a type of granulocyte derived from the myeloid stem ...

mast cell
s and causes activation of
complement A complement is often something that completes something else, or at least adds to it in some useful way. Thus it may be: * Complement (linguistics), a word or phrase having a particular syntactic role ** Subject complement, a word or phrase addi ...

complement
and kinins. This group includes the calpains. *''Basic proteases'' (or ''alkaline proteases'')


Enzymatic function and mechanism

Proteases are involved in digesting long protein chains into shorter fragments by splitting the
peptide bonds In organic chemistry Organic chemistry is a branch of chemistry that studies the structure, properties and reactions of organic compounds, which contain carbon in covalent bonding.Clayden, J.; Greeves, N. and Warren, S. (2012) ''Organic Chemistr ...
that link
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
residues. Some detach the terminal amino acids from the protein chain (
exopeptidases An exopeptidase is any peptidase that catalyst, catalyzes the cleavage of the terminal (or the penultimate) peptide bond; the process releases a single amino acid or dipeptide from the peptide chain. Depending on whether the amino acid is released ...
, such as
aminopeptidase Aminopeptidases are enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme ...
s,
carboxypeptidase A Carboxypeptidase A usually refers to the pancreatic exopeptidase that hydrolyzes Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, subst ...

carboxypeptidase A
); others attack internal peptide bonds of a protein (
endopeptidasesEndopeptidase or endoproteinase are proteolytic peptidases that break peptide bonds of nonterminal amino acid Amino acids are organic compounds that contain amino (–NH2) and Carboxylic acid, carboxyl (–COOH) functional groups, along with ...
, such as
trypsinTrypsin () is a serine protease of Trypsin, a typical serine protease. Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. ...
,
chymotrypsin Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme Digestive enzymes are a group of enzyme Enzym ...

chymotrypsin
,
pepsin Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, where ...

pepsin
,
papain Papain, also known as papaya proteinase I, is a () present in (''Carica papaya'') and (''Vasconcellea cundinamarcensis''). It is the namesake member of the family. It has wide ranging commercial applications in the leather, cosmetic, textil ...

papain
,
elastase 200px, Crystals of porcine elastase. In molecular biology, elastase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are ...

elastase
).


Catalysis

Catalysis Catalysis () is the process of increasing the of a by adding a substance known as a catalyst (). Catalysts are not consumed in the catalyzed reaction but can act repeatedly. Often only very small amounts of catalyst are required. The global ...

Catalysis
is achieved by one of two mechanisms: *Aspartic, glutamic, and metallo-proteases activate a water molecule, which performs a nucleophilic attack on the peptide bond to hydrolyze it. *Serine, threonine, and cysteine proteases use a nucleophilic residue (usually in a
catalytic triad A catalytic triad is a set of three coordinated amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen ...

catalytic triad
). That residue performs a nucleophilic attack to
covalent A covalent bond is a chemical bond A chemical bond is a lasting attraction between atom An atom is the smallest unit of ordinary matter In classical physics and general chemistry, matter is any substance that has mass and takes ...

covalent
ly link the protease to the substrate protein, releasing the first half of the product. This covalent acyl-enzyme intermediate is then hydrolyzed by activated water to complete catalysis by releasing the second half of the product and regenerating the free enzyme


Specificity

Proteolysis can be highly
promiscuous Promiscuity is the practice of engaging in sexual activity frequently with different Sexual partner, partners or being indiscriminate in the choice of sexual partners. The term can carry a moral judgment if the social ideal for sexual activity is m ...
such that a wide range of protein substrates are hydrolyzed. This is the case for digestive enzymes such as
trypsinTrypsin () is a serine protease of Trypsin, a typical serine protease. Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. ...
, which have to be able to cleave the array of proteins ingested into smaller peptide fragments. Promiscuous proteases typically bind to a single amino acid on the substrate and so only have specificity for that residue. For example,
trypsinTrypsin () is a serine protease of Trypsin, a typical serine protease. Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. ...
is specific for the sequences ...K\... or ...R\... ('\'=cleavage site). Conversely some proteases are highly specific and only cleave substrates with a certain sequence. Blood clotting (such as
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma-t ...
) and viral polyprotein processing (such as
TEV protease TEV protease (, ''Tobacco Etch Virus nuclear-inclusion-a endopeptidase'') is a highly sequence-specific cysteine protease from Tobacco etch virus, Tobacco Etch Virus (TEV). It is a member of the PA clan of chymotrypsin-like proteases. Due to its hi ...
) requires this level of specificity in order to achieve precise cleavage events. This is achieved by proteases having a long binding cleft or tunnel with several pockets that bind to specified residues. For example,
TEV protease TEV protease (, ''Tobacco Etch Virus nuclear-inclusion-a endopeptidase'') is a highly sequence-specific cysteine protease from Tobacco etch virus, Tobacco Etch Virus (TEV). It is a member of the PA clan of chymotrypsin-like proteases. Due to its hi ...
is specific for the sequence ...ENLYFQ\S... ('\'=cleavage site).


Degradation and autolysis

Proteases, being themselves proteins, are cleaved by other protease molecules, sometimes of the same variety. This acts as a method of regulation of protease activity. Some proteases are less active after autolysis (e.g.
TEV protease TEV protease (, ''Tobacco Etch Virus nuclear-inclusion-a endopeptidase'') is a highly sequence-specific cysteine protease from Tobacco etch virus, Tobacco Etch Virus (TEV). It is a member of the PA clan of chymotrypsin-like proteases. Due to its hi ...
) whilst others are more active (e.g.
trypsinogen Trypsinogen () is the precursor form (or zymogen) of trypsin, a digestive enzyme. It is produced by the pancreas and found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is cleaved to its active form, trypsin, by entero ...
).


Biodiversity of proteases

Proteases occur in all organisms, from
prokaryote A prokaryote () is a single-celled organism A unicellular organism, also known as a single-celled organism, is an organism In biology, an organism (from Ancient Greek, Greek: ὀργανισμός, ''organismos'') is any individual contig ...
s to
eukaryote Eukaryotes () are organism In biology, an organism () is any organic, life, living system that functions as an individual entity. All organisms are composed of cells (cell theory). Organisms are classified by taxonomy (biology), tax ...

eukaryote
s to
virus A virus is a that only inside the living of an . Viruses infect all , from animals and plants to s, including and . Since 's 1892 article describing a non-bacterial infecting tobacco plants and the discovery of the by in 1898, more ...

virus
. 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 The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibody, antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammatio ...

complement system
,
apoptosis Apoptosis (from Ancient Greek wikt:ἀπόπτωσις, ἀπόπτωσις, ''apóptōsis'', "falling off") is a form of programmed cell death that occurs in multicellular organisms. Biochemistry, Biochemical events lead to characteristic cell ...

apoptosis
pathways, and the invertebrate prophenoloxidase-activating cascade). Proteases can either break specific peptide bonds (''limited proteolysis''), depending on the
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
sequence of a protein, or completely break down a 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.


Plants

Protease-containing plant-solutions called have been in use for hundreds of years in
Europe Europe is a continent A continent is any of several large landmasses. Generally identified by convention (norm), convention rather than any strict criteria, up to seven geographical regions are commonly regarded as continents. Ordered ...

Europe
and the
Middle East The Middle East ( ar, الشرق الأوسط, ISO 233 The international standard An international standard is a technical standard A technical standard is an established norm (social), norm or requirement for a repeatable technical task whi ...

Middle East
for making kosher and halal Cheeses. Vegetarian rennet from ''
Withania coagulans ''Withania coagulans'' ( Sanskrit Sanskrit (, attributively , ''saṃskṛta-'', nominalization, nominally , ''saṃskṛtam'') is a classical language of South Asia belonging to the Indo-Aryan languages, Indo-Aryan branch of the Indo-Europea ...
'' has been in use for thousands of years as a
Ayurvedic Ayurveda () is an alternative medicine Alternative medicine is any practice that aims to achieve the healing effects of medicine Medicine is the Art (skill), art, science, and Praxis (process) , practice of caring for a patient and mana ...

Ayurvedic
remedy for digestion and diabetes in the Indian subcontinent. It is also used to make
Paneer Paneer (), also known as ponir () or Indian cottage cheese, is a fresh cheese, fresh acid-set cheese common in the Indian subcontinent (Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka) made from cow or buffalo milk. It is a Ch ...
. Plant genomes encode hundreds of proteases, largely of unknown function. Those with known function are largely involved in
developmental Development of the human body is the process of growth to maturity. The process begins with fertilization Fertilisation or fertilization (see spelling differences), also known as generative fertilisation, syngamy and impregnation, is the ...
regulation. Plant proteases also play a role in regulation of
photosynthesis Photosynthesis is a process used by plants and other organisms to into that, through , can later be released to fuel the organism's activities. Some of this chemical energy is stored in molecules, such as s and es, which are synthesized fro ...

photosynthesis
.


Animals

Proteases are used throughout an organism for various metabolic processes. Acid proteases secreted into the stomach (such as
pepsin Pepsin is an endopeptidase that breaks down proteins into smaller peptides. It is produced in the gastric chief cells of the stomach lining and is one of the main digestive enzymes in the digestive systems of humans and many other animals, where ...

pepsin
) and serine proteases present in the
duodenum The duodenum is the first section of the small intestine The small intestine or small bowel is an organ (anatomy), organ in the human gastrointestinal tract, gastrointestinal tract where most of the #Absorption, absorption of nutrients from foo ...

duodenum
(
trypsinTrypsin () is a serine protease of Trypsin, a typical serine protease. Serine proteases (or serine endopeptidases) are enzymes that cleave peptide bonds in proteins. Serine serves as the nucleophilic amino acid at the (enzyme's) active site. ...
and
chymotrypsin Chymotrypsin (, chymotrypsins A and B, alpha-chymar ophth, avazyme, chymar, chymotest, enzeon, quimar, quimotrase, alpha-chymar, alpha-chymotrypsin A, alpha-chymotrypsin) is a digestive enzyme Digestive enzymes are a group of enzyme Enzym ...

chymotrypsin
) enable us to digest the protein in food. Proteases present in blood serum (
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma-t ...
,
plasmin Plasmin is an important enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the en ...

plasmin
,
Hageman factor Coagulation factor XII, also known as Hageman factor, is a plasma protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast ar ...
, etc.) play an 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 200px, Crystals of porcine elastase. In molecular biology, elastase is an enzyme Enzymes () are proteins that act as biological catalysts (biocatalysts). Catalysts accelerate chemical reactions. The molecules upon which enzymes may act are ...

elastase
,
cathepsin G Cathepsin G is a protein that in humans is encoded by the ''CTSG'' gene. It is one of the three serine proteases of the chymotrypsin family that are stored in the azurophil granules, and also a member of the peptidase S1 protein family. Cathepsin G ...
) and play several different roles in metabolic control. Some snake venoms are also proteases, such as
pit viper The Crotalinae, commonly known as pit vipers,Mehrtens JM (1987). ''Living Snakes of the World in Color''. New York: Sterling Publishers. 480 pp. . crotaline snakes (named for the grc, κρόταλον ''krotalon''. castanet/rattle of a rattle ...

pit viper
haemotoxin and interfere with the victim's blood clotting cascade. Proteases determine the lifetime of other proteins playing important physiological roles 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 a complex cooperative action, proteases can catalyze
cascade Cascade, Cascades or Cascading may refer to: Science and technology Science *Cascade waterfalls, or series of waterfalls * Cascade, the CRISPR-associated complex for antiviral defense (a protein complex) * Cascade (grape), a type of fruit * Bioche ...
reactions, which result in rapid and efficient amplification of an organism's response to a physiological signal.


Bacteria

Bacteria secrete proteases to
hydrolyse Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution, elimination, and solvation reactions in which water is the nucleophile In chemistry, a nucleop ...
the peptide bonds in proteins and therefore break the proteins down into their constituent
amino acid Amino acids are organic compound , CH4; is among the simplest organic compounds. In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen chemical bond, bonds. Due to carbon's ability to Catenation, c ...

amino acid
s. Bacterial and fungal proteases are particularly important to the global
carbon Carbon (from la, carbo "coal") is a with the C and 6. It is lic and —making four s available to form s. It belongs to group 14 of the periodic table. Carbon makes up only about 0.025 percent of Earth's crust. Three occur naturally, ...

carbon
and
nitrogen Nitrogen is the chemical element upright=1.0, 500px, The chemical elements ordered by link=Periodic table In chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science ...

nitrogen
cycles in the recycling of proteins, and such activity tends to be regulated by nutritional signals in these organisms. 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. Bacteria contain proteases responsible for general protein quality control (e.g. the AAA+
proteasome Proteasomes are protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chain Peptides (from Greek language Greek (modern , romanized: ''Elliniká'', Ancient Greek, ancient , ''Hellēn ...

proteasome
) by degrading . A secreted bacterial protease may also act as an exotoxin, and be an example of a
virulence factor Virulence factors (preferably known as pathogenicity factors or effectors in plant science) are cellular structures, molecules and regulatory systems that enable microbial pathogens (bacteria, viruses, fungi, and protozoa) to achieve the following ...
in bacterial
pathogenesis Pathogenesis is the process by which a disease or Disease#Disorder, disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance. The word comes from the A ...

pathogenesis
(for example, exfoliative toxin). Bacterial exotoxic proteases destroy extracellular structures.


Viruses

The genomes of some viruses encode one massive
polyprotein Proteolysis is the breakdown of protein Proteins are large biomolecules or macromolecules that are comprised of one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, ...
, which needs a protease to cleave this into functional units (e.g. the
hepatitis C virus The hepatitis C virus (HCV) is a small (55–65 nm in size), enveloped, positive-sense single-stranded RNA virus An RNA virus is a virus A virus is a submicroscopic infectious agent that Viral replication, replicates only inside ...
virus and the
picornavirus Picornaviruses are a group of related nonenveloped RNA virus An RNA virus is a virus A virus is a submicroscopic infectious agent that Viral replication, replicates only inside the living Cell (biology), cells of an organism. Virus ...

picornavirus
es). These proteases (e.g.
TEV protease TEV protease (, ''Tobacco Etch Virus nuclear-inclusion-a endopeptidase'') is a highly sequence-specific cysteine protease from Tobacco etch virus, Tobacco Etch Virus (TEV). It is a member of the PA clan of chymotrypsin-like proteases. Due to its hi ...
) have high specificity and only cleave a very restricted set of substrate sequences. They are therefore a common target for protease inhibitors.


Uses

The field of protease research is enormous. Since 2004, approximately 8000
papers Paper is a thin, flat material produced by the compression of fibres. Paper(s) or The Paper may also refer to: Publishing and academia * Newspaper, a periodical publication * Paper (magazine), ''Paper'' (magazine), an American monthly fashion and ...
related to this field were published each year. Proteases are used in industry,
medicine Medicine is the science Science () is a systematic enterprise that builds and organizes knowledge Knowledge is a familiarity, awareness, or understanding of someone or something, such as facts ( descriptive knowledge), skills (proced ...

medicine
and as a basic biological research tool. Digestive proteases are part of many
laundry detergent Laundry detergent is a type of detergent A detergent is a surfactant Surfactants are compounds that lower the surface tension (or interfacial tension) between two liquids, between a gas and a liquid, or between a liquid and a solid. Sur ...
s and are also used extensively in the bread industry in bread improver. A variety of proteases are used medically both for their native function (e.g. controlling blood clotting) or for completely artificial functions (''e.g.'' for the targeted degradation of pathogenic proteins). Highly specific proteases such as
TEV protease TEV protease (, ''Tobacco Etch Virus nuclear-inclusion-a endopeptidase'') is a highly sequence-specific cysteine protease from Tobacco etch virus, Tobacco Etch Virus (TEV). It is a member of the PA clan of chymotrypsin-like proteases. Due to its hi ...
and
thrombin Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma-t ...
are commonly used to cleave fusion proteins and affinity tags in a controlled fashion.


Inhibitors

The activity of proteases is inhibited by protease inhibitor (biology), protease inhibitors. One example of protease inhibitors is the serpin superfamily. It includes alpha 1-antitrypsin (which protects the body from excessive effects of its own inflammation, inflammatory proteases), alpha 1-antichymotrypsin (which does likewise), C1-inhibitor (which protects the body from excessive protease-triggered activation of its own
complement system The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibody, antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammatio ...

complement system
), antithrombin (which protects the body from excessive coagulation), plasminogen activator inhibitor 1, plasminogen activator inhibitor-1 (which protects the body from inadequate coagulation by blocking protease-triggered fibrinolysis), 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 inhibitor (biology), protease inhibitors are not to be confused with the protease inhibitor (pharmacology), protease inhibitors used in antiretroviral therapy. Some virus (biology), viruses, with HIV/AIDS among them, depend on proteases in their reproductive cycle. Thus, protease inhibitor (pharmacology), protease inhibitors are developed as Antiviral drug, antiviral therapeutic agents. Other natural protease inhibitors are used as defense mechanisms. Common examples are the trypsin inhibitors found in the seeds of some plants, most notable for humans being soybeans, a major food crop, where they act to discourage predators. Raw soybeans are Soybean#Nutrition, toxic to many animals, including humans, until the protease inhibitors they contain have been denatured.


See also

* Ligase *Protease **cysteine protease, cysteine- **serine protease, serine- **threonine protease, threonine- **aspartic protease, aspartic- **glutamic protease, glutamic- **metalloprotease, metallo- *
PA clan The PA clan (protease, Proteases of mixed nucleophile, Protein superfamily, superfamily A) is the largest group of proteases with common ancestry as identified by structural homology. Members have a chymotrypsin-like fold and similar proteolysis me ...
* Convergent evolution * Proteolysis * Catalytic triad * The Proteolysis Map * Proteases in angiogenesis * Intramembrane proteases * Protease inhibitor (pharmacology) * Protease inhibitor (biology) * TopFIND - database of protease specificity, substrates, products and inhibitors * MEROPS - Database of protease evolutionary groups


References


External links


International Proteolysis Society

MEROPS - the peptidase database



Protease cutting predictor


(see als


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
* {{Authority control Proteases, EC 3.4, * Post-translational modification