Protease

Protease

A protease 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....

s are enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

s that degrade polypeptides

Protein

Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

. Cysteine proteases have a common catalytic mechanism

Catalysis

Catalysis is the change in rate of a chemical reaction due to the participation of a substance called a catalyst. Unlike other reagents that participate in the chemical reaction, a catalyst is not consumed by the reaction itself. A catalyst may participate in multiple chemical transformations....

 that involves a nucleophilic

Nucleophile

A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 cysteine

Cysteine

Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 thiol

Thiol

In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 in a catalytic dyad. The first step is deprotonation

Protonation

In chemistry, protonation is the addition of a proton to an atom, molecule, or ion. Some classic examples include*the protonation of water by sulfuric acid:*the protonation of isobutene in the formation of a carbocation:2C=CH2 + HBF4 → 3C+ + BF4−*the protonation of ammonia in the...

 of a thiol

Thiol

In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 in the enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

's active site by an adjacent amino acid

Amino acid

Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 with a basic side chain

Side chain

In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...

, usually a histidine

Histidine

Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 residue. The next step is nucleophilic

Nucleophile

A nucleophile is a species that donates an electron-pair to an electrophile to form a chemical bond in a reaction. All molecules or ions with a free pair of electrons can act as nucleophiles. Because nucleophiles donate electrons, they are by definition Lewis bases.Nucleophilic describes the...

 attack by the deprotonated cysteine's anionic sulfur

Sulfur

Sulfur or sulphur is the chemical element with atomic number 16. In the periodic table it is represented by the symbol S. It is an abundant, multivalent non-metal. Under normal conditions, sulfur atoms form cyclic octatomic molecules with chemical formula S8. Elemental sulfur is a bright yellow...

 on the substrate

Substrate (biochemistry)

In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 carbonyl

Carbonyl

In organic chemistry, a carbonyl group is a functional group composed of a carbon atom double-bonded to an oxygen atom: C=O. It is common to several classes of organic compounds, as part of many larger functional groups....

 carbon

Carbon

Carbon is the chemical element with symbol C and atomic number 6. As a member of group 14 on the periodic table, it is nonmetallic and tetravalent—making four electrons available to form covalent chemical bonds...

. In this step, a fragment of the substrate is released with an amine

Amine

Amines are organic compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are derivatives of ammonia, wherein one or more hydrogen atoms have been replaced by a substituent such as an alkyl or aryl group. Important amines include amino acids, biogenic amines,...

 terminus, the histidine

Histidine

Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...

 residue in the protease

Protease

A protease 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....

 is restored to its deprotonated form, and a thioester

Thioester

Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.-Synthesis:...

 intermediate linking the new carboxy-terminus of the substrate to the cysteine thiol

Thiol

In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 is formed. Therefore they are also sometimes referred to as thiol proteases. The thioester

Thioester

Thioesters are compounds with the functional group C-S-CO-C. They are the product of esterification between a carboxylic acid and a thiol. Thioesters are widespread in biochemistry, the best-known derivative being acetyl-CoA.-Synthesis:...

 bond is subsequently hydrolyzed

Hydrolysis

Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...

 to generate a carboxylic acid

Carboxylic acid

Carboxylic acids are organic acids characterized by the presence of at least one carboxyl group. The general formula of a carboxylic acid is R-COOH, where R is some monovalent functional group...

 moiety on the remaining substrate fragment, while regenerating the free enzyme

Enzyme

Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

.

Cysteine proteases are commonly encountered in fruits including papaya

Papaya

The papaya , papaw, or pawpaw is the fruit of the plant Carica papaya, the sole species in the genus Carica of the plant family Caricaceae...

, pineapple

Pineapple

Pineapple is the common name for a tropical plant and its edible fruit, which is actually a multiple fruit consisting of coalesced berries. It was given the name pineapple due to its resemblance to a pine cone. The pineapple is by far the most economically important plant in the Bromeliaceae...

, fig

Common fig

The Common fig is a deciduous tree growing to heights of up to 6 m in the genus Ficus from the family Moraceae known as Common fig tree. It is a temperate species native to the Middle East.-Description:...

 and kiwifruit

Kiwifruit

The kiwifruit, often shortened to kiwi in many parts of the world, is the edible berry of a cultivar group of the woody vine Actinidia deliciosa and hybrids between this and other species in the genus Actinidia....

. The proportion of protease tends to be higher when the fruit

Fruit

In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...

 is unripe. In fact, dozens of latices

Latex

Latex is the stable dispersion of polymer microparticles in an aqueous medium. Latexes may be natural or synthetic.Latex as found in nature is a milky fluid found in 10% of all flowering plants . It is a complex emulsion consisting of proteins, alkaloids, starches, sugars, oils, tannins, resins,...

 of different plant families

Family (biology)

In biological classification, family is* a taxonomic rank. Other well-known ranks are life, domain, kingdom, phylum, class, order, genus, and species, with family fitting between order and genus. As for the other well-known ranks, there is the option of an immediately lower rank, indicated by the...

 are known to contain cysteine proteases.
Cysteine proteases are used as an ingredient in meat tenderizer

Meat tenderizer

A meat tenderizer is hand-powered tool used to tenderize slabs of meat in preparation for cooking the meat. Although a meat tenderizer can be made out of virtually any object there are three types that manufactured specifically for tenderizing meat. The first, most common, is a tool that resembles...

s.

Biological importance

Cysteine proteases play multi-faceted roles, virtually in every aspect of physiology and development, in plants such as in the growth and development, in senescence

Senescence

Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...

 and programmed cell death

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, in accumulation and mobilization of storage proteins such as in seeds

SEEDS

SEEDS is a voluntary organisation registered under the Societies Act of India....

. In addition, they are involved in signalling pathways and in the response to biotic

Biotic component

Biotic components are the living things that shape an ecosystem. A biotic factor is any living component that affects another organism, including animals that consume the organism in question, and the living food that the organism consumes. Each biotic factor needs energy to do work and food for...

 and abiotic stresses. In humans they are responsible for apoptosis

Apoptosis

Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...

, MHC class II immune responses, prohormone

Prohormone

A prohormone is a substance that is a precursor to a hormone, usually having minimal hormonal effect by itself. The term has been used in medical science since the middle of the 20th century. The primary function of a prohormone is to enhance the strength of the hormone that already occurs in the...

 processing, and extracellular matrix

Extracellular matrix

In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...

 remodeling important to bone

Bone

Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...

 development. The ability of macrophages and other cells to mobilize elastolytic cysteine proteases to their surfaces under specialized conditions may also lead to accelerated collagen

Collagen

Collagen is a group of naturally occurring proteins found in animals, especially in the flesh and connective tissues of mammals. It is the main component of connective tissue, and is the most abundant protein in mammals, making up about 25% to 35% of the whole-body protein content...

 and elastin

Elastin

Elastin is a protein in connective tissue that is elastic and allows many tissues in the body to resume their shape after stretching or contracting. Elastin helps skin to return to its original position when it is poked or pinched. Elastin is also an important load-bearing tissue in the bodies of...

 degradation at sites of inflammation

Inflammation

Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...

 in diseases such as atherosclerosis

Atherosclerosis

Atherosclerosis is a condition in which an artery wall thickens as a result of the accumulation of fatty materials such as cholesterol...

 and emphysema

Emphysema

Emphysema is a long-term, progressive disease of the lungs that primarily causes shortness of breath. In people with emphysema, the tissues necessary to support the physical shape and function of the lungs are destroyed. It is included in a group of diseases called chronic obstructive pulmonary...

.

In several traditional medicine

Traditional medicine

Traditional medicine comprises unscientific knowledge systems that developed over generations within various societies before the era of modern medicine...

s the fruits or latex

Latex

Latex is the stable dispersion of polymer microparticles in an aqueous medium. Latexes may be natural or synthetic.Latex as found in nature is a milky fluid found in 10% of all flowering plants . It is a complex emulsion consisting of proteins, alkaloids, starches, sugars, oils, tannins, resins,...

 of papaya

Papaya

The papaya , papaw, or pawpaw is the fruit of the plant Carica papaya, the sole species in the genus Carica of the plant family Caricaceae...

, pineapple

Pineapple

Pineapple is the common name for a tropical plant and its edible fruit, which is actually a multiple fruit consisting of coalesced berries. It was given the name pineapple due to its resemblance to a pine cone. The pineapple is by far the most economically important plant in the Bromeliaceae...

 and fig

Common fig

The Common fig is a deciduous tree growing to heights of up to 6 m in the genus Ficus from the family Moraceae known as Common fig tree. It is a temperate species native to the Middle East.-Description:...

 are widely used for treatment of intestinal worm infections both in humans and livestock animals

Livestock

Livestock refers to one or more domesticated animals raised in an agricultural setting to produce commodities such as food, fiber and labor. The term "livestock" as used in this article does not include poultry or farmed fish; however the inclusion of these, especially poultry, within the meaning...

. Plant cysteine proteinases isolated from these plants have been found to have high proteolytic activities

Proteolysis

Proteolysis is the directed degradation of proteins by cellular enzymes called proteases or by intramolecular digestion.-Purposes:Proteolysis is used by the cell for several purposes...

 that are known to digest

Digest

Digest can refer to any of the following:*A condensed collection or compendium of writings:**Pandects, or "The Digest", a digest of Roman law**A tax digest...

 nematode cuticles

Cuticle

A cuticle , or cuticula, is a term used for any of a variety of tough but flexible, non-mineral outer coverings of an organism, or parts of an organism, that provide protection. Various types of "cuticles" are non-homologous; differing in their origin, structure, function, and chemical composition...

, with very low toxicity. Successful results have been reported against nematodes such as Heligmosomoides bakeri, Trichinella spiralis

Trichinella spiralis

Trichinella spiralis is a nematode parasite, occurring in rats, pigs, bears and humans, and is responsible for the disease trichinosis. It is sometimes referred to as the "pork worm" due to it being found commonly in undercooked pork products...

, Nippostrongylus brasiliensis

Nippostrongylus brasiliensis

Nippostrongylus brasiliensis is gastrointestinal nematode parasite of rats.-Life cycle:The life cycle is similar to that of the human hookworms, Necator americanus and Ancylostoma duodenale....

, Trichuris muris

Trichuris muris

Trichuris muris is a nematode parasite of mice. It is very similar to the human roundworm parasite Trichuris trichiura due to its immunological reactivity when crossed , and so is often used in related studies.. Ingesting material that contains embryonated eggs allows for transmission and infection...

, and Ancylostoma ceylanicum; the tapeworm Rodentolepis microstoma and the porcine acanthocephalan parasite

Acanthocephala

Acanthocephala is a phylum of parasitic worms known as acanthocephales, thorny-headed worms, or spiny-headed worms, characterized by the presence of an evertable proboscis, armed with spines, which it uses to pierce and hold the gut wall of its host...

 Macracanthorynchus hirundinaceus.

Examples of cysteine proteases

• Actinidain
  Actinidain
  Actinidain is a type of cysteine protease enzyme found in fruits including kiwifruit , pineapple, mango, banana and papaya. This enzyme is part of the papain-like peptidase C1 family....
  
  
• Bromelain
  Bromelain
  Bromelain is a pineapple extract thought to be effective for reducing swelling , especially of the nose and sinuses, after surgery or injury. It may also be used for a variety of other effects that remain scientifically unconfirmed and not authorized by regulatory authorities like the Food and Drug...
  
  
• Calpains
• Caspases
• Cathepsins
• Mir1-CP
• Papain
  Papain
  Papain, also known as papaya proteinase I, is a cysteine protease enzyme present in papaya and mountain papaya .-Papain family:...
  
  

Protease regulation

Proteases are usually synthesized as large precursor proteins called zymogens, such as the serine protease

Serine protease

Serine proteases are enzymes that cleave peptide bonds in proteins, in which serine serves as the nucleophilic amino acid at the active site.They are found ubiquitously in both eukaryotes and prokaryotes...

 precursors trypsinogen

Trypsinogen

Trypsinogen is the precursor form or zymogen of the pancreatic enzyme trypsin. It is found in pancreatic juice, along with amylase, lipase, and chymotrypsinogen. It is activated by enteropeptidase, which is found in the intestinal mucosa, to form trypsin. Once activated, the trypsin can activate...

 and chymotrypsinogen

Chymotrypsinogen

Chymotrypsinogen is a precursor of the digestive enzyme chymotrypsin.This molecule is inactive and must be cleaved by trypsin, and then by other...

, and the aspartic protease precursor pepsinogen. The protease is activated by removal of an inhibitory segment or protein. Activation occurs once the protease is delivered to a specific intracellular compartment (e.g. lysosome

Lysosome

thumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...

) or extracellular environment (e.g. stomach

Stomach

The stomach is a muscular, hollow, dilated part of the alimentary canal which functions as an important organ of the digestive tract in some animals, including vertebrates, echinoderms, insects , and molluscs. It is involved in the second phase of digestion, following mastication .The stomach is...

). This system prevents the cell

Cell (biology)

The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 that produces the protease from being damaged by it.

Protease inhibitor

Enzyme inhibitor

An enzyme inhibitor is a molecule that binds to enzymes and decreases their activity. Since blocking an enzyme's activity can kill a pathogen or correct a metabolic imbalance, many drugs are enzyme inhibitors. They are also used as herbicides and pesticides...

s are usually proteins with domains that enter or block a protease active site

Active site

In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...

 to prevent substrate

Substrate (biochemistry)

In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 access. In competitive inhibition, the inhibitor binds to the active site, thus preventing enzyme-substrate interaction. In non-competitive inhibition, the inhibitor binds to an allosteric site

Allosteric regulation

In biochemistry, allosteric regulation is the regulation of an enzyme or other protein by binding an effector molecule at the protein's allosteric site . Effectors that enhance the protein's activity are referred to as allosteric activators, whereas those that decrease the protein's activity are...

, which alters the active site and makes it inaccessible to the substrate.

Examples of protease inhibitors

• Serpin
  Serpin
  Serpins are a group of proteins with similar structures that were first identified as a set of proteins able to inhibit proteases. The acronym serpin was originally coined because many serpins inhibit chymotrypsin-like serine proteases .The first members of the serpin superfamily to be extensively...
  
  s
• Stefins
• IAP
  Inhibitor of apoptosis
  The Inhibitors of Apoptosis are a family of functionally- and structurally-related proteins, which serve as endogenous inhibitors of programmed cell death . A common feature of all IAPs is the presence of a BIR in one to three copies...
  
  s
• TIMPs

External links

• The MEROPS
  Merops
  Merops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
  
  online database for peptidases and their inhibitors: Cysteine Peptidases