A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
that
catalyzes (increases
reaction rate
The reaction rate or rate of reaction is the speed at which a chemical reaction takes place, defined as proportional to the increase in the concentration of a product per unit time and to the decrease in the concentration of a reactant per uni ...
or "speeds up")
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
, breaking down
proteins
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
into smaller
polypeptide
Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides.
...
s or single
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s, and spurring the formation of new protein products.
They do this by cleaving the
peptide bonds 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, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
, a reaction where
water
Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as ...
breaks
bonds. Proteases are involved in many biological functions, including
digestion
Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small intest ...
of ingested proteins,
protein catabolism (breakdown of old proteins),
and
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
.
In the absence of functional accelerants, proteolysis would be very slow, taking hundreds of
years. Proteases can be found in all forms of life and
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsk ...
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 biological molecule, an " enzyme". Most enzymes are proteins, and most such processes are chemical reactions. Within the enzyme, generally catalysis occurs at a localized site, call ...
s.
Hierarchy of proteases
Based on catalytic residue
Proteases can be classified into seven broad groups:
*
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.
They are found ubiquitously in both eukaryotes and prokaryotes. Seri ...
s - using a
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...
alcohol
Alcohol most commonly refers to:
* Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom
* Alcohol (drug), an intoxicant found in alcoholic drinks
Alcohol may also refer to:
Chemicals
* Ethanol, one of sev ...
*
Cysteine protease
Cysteine proteases, also known as thiol proteases, are hydrolase enzymes that degrade proteins. These proteases share a common catalytic mechanism that involves a nucleophilic cysteine thiol in a catalytic triad or dyad.
Discovered by Gopal ...
s - using a
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
thiol
In organic chemistry, a thiol (; ), or thiol derivative, is any organosulfur compound of the form , where R represents an alkyl or other organic substituent. The functional group itself is referred to as either a thiol group or a sulfhydryl gro ...
*
Threonine proteases - using a
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...
secondary alcohol
*
Aspartic proteases - using an
aspartate
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
*
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 ...
s - using a
glutamate
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
carboxylic acid
In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an R-group. The general formula of a carboxylic acid is or , with R referring to the alkyl, alkenyl, aryl, or other group. Carboxyli ...
*
Metalloproteases - using a
metal
A metal (from ancient Greek, Greek μέταλλον ''métallon'', "mine, quarry, metal") is a material that, when freshly prepared, polished, or fractured, shows a lustrous appearance, and conducts electrical resistivity and conductivity, e ...
, usually
zinc
Zinc is a chemical element with the symbol Zn and atomic number 30. Zinc is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodi ...
*
Asparagine peptide lyases - using an
asparagine
Asparagine (symbol Asn or N) is an α-amino acid that is 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 group (which is in the depro ...
to perform an
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 that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...
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 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 or protein cha ...
involves making an
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
residue that has the
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
and threonine (proteases) or a water molecule (
aspartic acid
Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. Like all other amino acids, it contains an amino group and a carboxylic acid. Its α-amino group is in the pro ...
, metallo- and acid proteases) nucleophilic so that it can attack the peptide
carbonyl group. One way to make a nucleophile is by a
catalytic triad, where a
histidine
Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated –NH3+ form under biological conditions), a carboxylic acid group (which is in the ...
residue is used to activate
serine
Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − for ...
,
cysteine
Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile.
When present as a deprotonated catalytic residue, some ...
, or
threonine
Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COO� ...
as a nucleophile. This is not an evolutionary grouping, however, as the nucleophile types have
evolved convergently 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, elimination, and solvation reactions in which water is the nucleophile.
Biological hydrolysi ...
, it performs an
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 where P indicates a mixture of nucleophile families). Within each 'clan', proteases are classified into
families 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.
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
,
elastase,
thrombin 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
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.
This group includes the
calpains
A calpain (; , ) is a protein belonging to the family of calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes) expressed ubiquitously in mammals and many other organisms. Calpains constitute the C2 family of protease clan CA ...
.
*''Basic proteases'' (or ''alkaline proteases'')
Enzymatic function and mechanism
Proteases are involved in
digesting
Digestion is the breakdown of large insoluble food molecules into small water-soluble food molecules so that they can be absorbed into the watery blood plasma. In certain organisms, these smaller substances are absorbed through the small intest ...
long protein chains into shorter fragments by splitting the
peptide bonds that link
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
residues. Some detach the terminal amino acids from the protein chain (
exopeptidases
An exopeptidase is any peptidase that catalyzes the cleavage of the terminal (or the penultimate) peptide bond; the process releases a single amino acid, dipeptide or a tripeptide from the peptide chain. Depending on whether the amino acid is re ...
, such as
aminopeptidase
Aminopeptidases are enzymes that catalyze the cleavage of amino acids from the amino terminus ( N-terminus) of proteins or peptides (exopeptidases). They are widely distributed throughout the animal and plant kingdoms and are found in many sub ...
s,
carboxypeptidase A); others attack internal peptide bonds of a protein (
endopeptidases, such as
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
,
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 component of pancreatic juice acting in the duod ...
,
pepsin,
papain
Papain, also known as papaya proteinase I, is a cysteine protease () enzyme present in papaya (''Carica papaya'') and mountain papaya (''Vasconcellea cundinamarcensis''). It is the namesake member of the papain-like protease family.
It has wide ...
,
elastase).
Catalysis
Catalysis
Catalysis () is the process of increasing the rate of a chemical reaction by adding a substance known as a catalyst (). Catalysts are not consumed in the reaction and remain unchanged after it. If the reaction is rapid and the catalyst recyc ...
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). That residue performs a nucleophilic attack to
covalent
A covalent bond is a chemical bond that involves the sharing of electrons to form electron pairs between atoms. These electron pairs are known as shared pairs or bonding pairs. The stable balance of attractive and repulsive forces between atom ...
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 such that a wide range of protein substrates are hydrolyzed. This is the case for digestive enzymes such as
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
, 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,
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
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) and viral polyprotein processing (such as
TEV protease) 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 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) 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 ent ...
).
Biodiversity of proteases
Proteases occur in all organisms, from
prokaryote
A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Con ...
s to
eukaryote
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacter ...
s to
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsk ...
. 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 antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
,
apoptosis
Apoptosis (from grc, ἀπόπτωσις, apóptōsis, 'falling off') is a form of programmed cell death that occurs in multicellular organisms. Biochemical events lead to characteristic cell changes ( morphology) and death. These changes in ...
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 compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
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 ''
vegetarian rennet'' have been in use for hundreds of years in
Europe
Europe is a large peninsula conventionally considered a continent in its own right because of its great physical size and the weight of its history and traditions. Europe is also considered a Continent#Subcontinents, subcontinent of Eurasia ...
and the
Middle East
The Middle East ( ar, الشرق الأوسط, ISO 233: ) is a geopolitical region commonly encompassing Arabian Peninsula, Arabia (including the Arabian Peninsula and Bahrain), Anatolia, Asia Minor (Asian part of Turkey except Hatay Pro ...
for making
kosher and halal Cheeses. Vegetarian rennet from ''
Withania coagulans'' has been in use for thousands of years as a
Ayurvedic
Ayurveda () is an alternative medicine system with historical roots in the Indian subcontinent. The theory and practice of Ayurveda is pseudoscientific. Ayurveda is heavily practiced in India and Nepal, where around 80% of the population repo ...
remedy for digestion and diabetes in the Indian subcontinent. It is also used to make
Paneer.
Plant genomes encode hundreds of proteases, largely of unknown function. Those with known function are largely involved in
developmental regulation. Plant proteases also play a role in regulation of
photosynthesis
Photosynthesis is a process used by plants and other organisms to convert light energy into chemical energy that, through cellular respiration, can later be released to fuel the organism's activities. Some of this chemical energy is stored in ...
.
Animals
Proteases are used throughout an organism for various metabolic processes. Acid proteases secreted into the stomach (such as
pepsin) and serine proteases present in the
duodenum
The duodenum is the first section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear, and the terms anterior intestine or proximal intestine m ...
(
trypsin
Trypsin is an enzyme in the first section of the small intestine that starts the digestion of protein molecules by cutting these long chains of amino acids into smaller pieces. It is a serine protease from the PA clan superfamily, found in the d ...
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 component of pancreatic juice acting in the duod ...
) enable us to digest the protein in food. Proteases present in blood serum (
thrombin,
plasmin,
Hageman factor
Coagulation factor XII, also known as Hageman factor, is a plasma protein. It is the zymogen form of factor XIIa, an enzyme () of the serine protease (or serine endopeptidase) class. In humans, factor XII is encoded by the ''F12'' gene.
Stru ...
, 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,
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 (from grc, κρόταλον ''krotalon'' castanet), or pit adders, are a subfa ...
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
* Bioc ...
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.
Biological hydrolysi ...
the peptide bonds in proteins and therefore break the proteins down into their constituent
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
s. Bacterial and fungal proteases are particularly important to the global
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon ma ...
and
nitrogen
Nitrogen is the chemical element with the symbol N and atomic number 7. Nitrogen is a nonmetal and the lightest member of group 15 of the periodic table, often called the pnictogens. It is a common element in the universe, estimated at se ...
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 complexes which degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that help such reactions are called proteases.
Proteasomes are part of a major mechanism by whi ...
) by degrading
unfolded or misfolded proteins.
A secreted bacterial protease may also act as an exotoxin, and be an example of a
virulence factor in bacterial
pathogenesis (for example,
exfoliative toxin). Bacterial exotoxic proteases destroy extracellular structures.
Viruses
The genomes of some viruses encode one massive
polyprotein, 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 of the family '' Flaviviridae''. The hepatitis C virus is the cause of hepatitis C and some cancers such as liver cancer (hepatoc ...
and the
picornaviruses). These proteases (e.g.
TEV protease) have high specificity and only cleave a very restricted set of substrate sequences. They are therefore a common target for
protease inhibitors.
Archaea
Archaea
Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaeba ...
use proteases to regulate various cellular processes from
cell-signaling,
metabolism
Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run ...
,
secretion 440px
Secretion is the movement of material from one point to another, such as a secreted chemical substance from a cell or gland. In contrast, excretion is the removal of certain substances or waste products from a cell or organism. The classic ...
and protein quality control.
Only two ATP-dependent proteases are found in archaea: the membrane associated LonB protease and a soluble
20S proteosome complex .
Uses
The field of protease research is enormous. Since 2004, approximately 8000
papers related to this field were published each year. Proteases are used in industry,
medicine
Medicine is the science and practice of caring for a patient, managing the diagnosis, prognosis, prevention, treatment, palliation of their injury or disease, and promoting their health. Medicine encompasses a variety of health care pr ...
and as a basic biological research tool.
Digestive proteases are part of many
laundry detergents and are also used extensively in the bread industry in
bread improver
A dough conditioner, flour treatment agent, improving agent or bread improver is any ingredient or chemical added to bread dough to strengthen its texture or otherwise improve it in some way. Dough conditioners may include enzymes, yeast nutrien ...
. 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 and
thrombin are commonly used to cleave
fusion protein
Fusion proteins or chimeric (kī-ˈmir-ik) proteins (literally, made of parts from different sources) are proteins created through the joining of two or more genes that originally coded for separate proteins. Translation of this '' fusion gene'' ...
s and
affinity tags in a controlled fashion.
Inhibitors
The activity of proteases is inhibited by
protease inhibitors. One example of protease inhibitors is the
serpin superfamily. It includes
alpha 1-antitrypsin
Alpha-1 antitrypsin or α1-antitrypsin (A1AT, α1AT, A1A, or AAT) is a protein belonging to the serpin superfamily. It is encoded in humans by the ''SERPINA1'' gene. A protease inhibitor, it is also known as alpha1–proteinase inhibitor (A1PI) ...
(which protects the body from excessive effects of its own
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 antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and ...
),
antithrombin (which protects the body from excessive
coagulation
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
),
plasminogen activator inhibitor-1 (which protects the body from inadequate coagulation by blocking protease-triggered
fibrinolysis), and
neuroserpin
Neuroserpin is a protein that in humans is encoded by the ''SERPINI1'' gene.
It is associated with Familial encephalopathy with neuroserpin inclusion bodies.
Serine protease inhibitors of the serpin superfamily are involved in many cellular pr ...
.
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
virus
A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea.
Since Dmitri Ivanovsk ...
es, with
HIV/AIDS
Human immunodeficiency virus infection and acquired immunodeficiency syndrome (HIV/AIDS) is a spectrum of conditions caused by infection with the human immunodeficiency virus (HIV), a retrovirus. Following initial infection an individual ...
among them, depend on proteases in their reproductive cycle. Thus,
protease inhibitors are developed as
antiviral
Antiviral drugs are a class of medication used for treating viral infections. Most antivirals target specific viruses, while a broad-spectrum antiviral is effective against a wide range of viruses. Unlike most antibiotics, antiviral drugs do n ...
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
toxic
Toxicity is the degree to which a chemical substance or a particular mixture of substances can damage an organism. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a sub ...
to many animals, including humans, until the protease inhibitors they contain have been denatured.
See also
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Ligase
*Protease
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cysteine-
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serine-
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threonine-
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aspartic-
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glutamic-
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metallo-
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PA clan
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Convergent evolution
Convergent evolution is the independent evolution of similar features in species of different periods or epochs in time. Convergent evolution creates analogous structures that have similar form or function but were not present in the last com ...
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Proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
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Catalytic triad
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The Proteolysis Map
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Proteases in angiogenesis Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during n ...
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Intramembrane protease Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral ...
s
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Protease inhibitor (pharmacology)
Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS and hepatitis C. These protease inhibitors prevent viral replic ...
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Protease inhibitor (biology)
In biology and biochemistry, protease inhibitors, or antiproteases, are molecules that inhibit the function of proteases ( enzymes that aid the breakdown of proteins). Many naturally occurring protease inhibitors are proteins.
In medicine, ' ...
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TopFIND
TopFIND is the Termini oriented protein Function Inferred Database (TopFIND) is an integrated knowledgebase focused on protein termini, their formation by proteases and functional implications. It contains information about the processing and t ...
- database of protease specificity, substrates, products and inhibitors
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MEROPS
MEROPS is an online database for peptidases (also known as proteases, proteinases and proteolytic enzymes) and their inhibitors. The classification scheme for peptidases was published by Rawlings & Barrett in 1993, and that for protein inhibitors ...
- Database of protease evolutionary groups
References
External links
International Proteolysis SocietyMEROPS - the peptidase databaseProtease cutting predictor(see als
Proteolysis MAP from Center for Proteolytic PathwaysProteolysis Cut Site database - curated expert annotation from usersProtease cut sites graphical interfaceTopFIND protease database covering cut sites, substrates and protein termini*
{{Authority control
Proteases,
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Post-translational modification