2XZZ
52-484: 7051 21816 ENSG00000092295 ENSG00000285348 ENSMUSG00000022218 P22735 Q9JLF6 NM_000359 NM_001161714 NM_001161715 NM_019984 NP_000350 NP_001155186 NP_001155187 NP_064368 Protein-glutamine gamma-glutamyltransferase K is a transglutaminase enzyme that in humans is encoded by the TGM1 gene . Keratinocyte transglutaminase enzymes serve to specifically catalyze
104-402: A cofactor . Transglutaminases were first described in 1959. The exact biochemical activity of transglutaminases was discovered in blood coagulation protein factor XIII in 1968. Nine transglutaminases have been characterised in humans, eight of which catalyse transamidation reactions. These TGases have a three or four-domain organization, with immunoglobulin -like domains surrounding
156-412: A slippery sequence in the mRNA that codes for the polypeptide causes ribosomal frameshifting , leading to two different lengths of peptidic chains ( a and ab ) at an approximately fixed ratio. Many proteins and hormones are synthesized in the form of their precursors - zymogens , proenzymes , and prehormones . These proteins are cleaved to form their final active structures. Insulin , for example,
208-521: A ubiquitin -dependent process that targets unwanted proteins to proteasome . The autophagy -lysosomal pathway is normally a non-selective process, but it may become selective upon starvation whereby proteins with peptide sequence KFERQ or similar are selectively broken down. The lysosome contains a large number of proteases such as cathepsins . The ubiquitin-mediated process is selective. Proteins marked for degradation are covalently linked to ubiquitin. Many molecules of ubiquitin may be linked in tandem to
260-541: A " pasta " made from over 95% shrimp thanks to transglutaminase. 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 proteases , but may also occur by intra-molecular digestion. Proteolysis in organisms serves many purposes; for example, digestive enzymes break down proteins in food to provide amino acids for
312-545: A Cys-Asp diad. Transglutaminases form extensively cross-linked, generally insoluble protein polymers. These biological polymers are indispensable for an organism to create barriers and stable structures. Examples are blood clots (coagulation factor XIII ), skin , and hair . The catalytic reaction is generally viewed as being irreversible, and must be closely monitored through extensive control mechanisms. Deficiency of factor XIII (a rare genetic condition) predisposes to hemorrhage ; concentrated enzyme can be used to correct
364-487: A binding agent to improve the texture of protein-rich foods such as surimi or ham . Thrombin – fibrinogen "meat glue" from bovine and porcine sources was banned throughout the European Union as a food additive in 2010. Transglutaminase remains allowed and is not required to be declared, as it is considered a processing aid and not an additive which remains present in the final product. Transglutaminase
416-411: A cascade of sequential proteolytic activation of many specific proteases, resulting in blood coagulation. The complement system of the immune response also involves a complex sequential proteolytic activation and interaction that result in an attack on invading pathogens. Protein degradation may take place intracellularly or extracellularly. In digestion of food, digestive enzymes may be released into
468-503: A positively charged residue ( arginine and lysine ); chymotrypsin cleaves the bond after an aromatic residue ( phenylalanine , tyrosine , and tryptophan ); elastase cleaves the bond after a small non-polar residue such as alanine or glycine. In order to prevent inappropriate or premature activation of the digestive enzymes (they may, for example, trigger pancreatic self-digestion causing pancreatitis ), these enzymes are secreted as inactive zymogen. The precursor of pepsin , pepsinogen ,
520-506: A protein destined for degradation. The polyubiquinated protein is targeted to an ATP-dependent protease complex, the proteasome. The ubiquitin is released and reused, while the targeted protein is degraded. Different proteins are degraded at different rates. Abnormal proteins are quickly degraded, whereas the rate of degradation of normal proteins may vary widely depending on their functions. Enzymes at important metabolic control points may be degraded much faster than those enzymes whose activity
572-416: A protein, and proteins with segments rich in proline , glutamic acid , serine , and threonine (the so-called PEST proteins ) have short half-life. Other factors suspected to affect degradation rate include the rate deamination of glutamine and asparagine and oxidation of cystein , histidine , and methionine, the absence of stabilizing ligands, the presence of attached carbohydrate or phosphate groups,
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#1732797306758624-503: A substantial deficit in keratinocyte transglutaminase activity. It was concluded that those afflicted, display a decrease in activity of the enzyme, as a result of a lessened amount of transcription of the human TGK gene. This lack of protein stems from a common mutation of the TGK gene, which exists in two possible variants, found at the TGM1 locus on the 14q11 chromosome, as exhibited amongst all
676-399: A ubiquitin-mediated proteolytic pathway. Caspases are an important group of proteases involved in apoptosis or programmed cell death . The precursors of caspase, procaspase, may be activated by proteolysis through its association with a protein complex that forms apoptosome , or by granzyme B , or via the death receptor pathways. Autoproteolysis takes place in some proteins, whereby
728-505: Is Transglutaminases can also join a primary amine ( RNH 2 ) to the side chain carboxyamide group of a protein/peptide bound glutamine residue thus forming an isopeptide bond These enzymes can also deamidate glutamine residues to glutamic acid residues in the presence of water Transglutaminase isolated from Streptomyces mobaraensis - bacteria for example, is a calcium -independent enzyme. Mammalian transglutaminases among other transglutaminases require Ca ions as
780-419: Is also used in molecular gastronomy to meld new textures with existing tastes. Besides these mainstream uses, transglutaminase has been used to create some unusual foods. British chef Heston Blumenthal is credited with the introduction of transglutaminase into modern cooking. Wylie Dufresne , chef of New York's avant-garde restaurant wd~50 , was introduced to transglutaminase by Blumenthal, and invented
832-401: Is largely constant under all physiological conditions. One of the most rapidly degraded proteins is ornithine decarboxylase , which has a half-life of 11 minutes. In contrast, other proteins like actin and myosin have a half-life of a month or more, while, in essence, haemoglobin lasts for the entire life-time of an erythrocyte . The N-end rule may partially determine the half-life of
884-575: Is left intact. Certain chemicals cause proteolysis only after specific residues, and these can be used to selectively break down a protein into smaller polypeptides for laboratory analysis. For example, cyanogen bromide cleaves the peptide bond after a methionine . Similar methods may be used to specifically cleave tryptophanyl , aspartyl , cysteinyl , and asparaginyl peptide bonds. Acids such as trifluoroacetic acid and formic acid may be used for cleavage. Like other biomolecules, proteins can also be broken down by high heat alone. At 250 °C,
936-399: Is necessary to break down proteins into small peptides (tripeptides and dipeptides) and amino acids so they can be absorbed by the intestines, and the absorbed tripeptides and dipeptides are also further broken into amino acids intracellularly before they enter the bloodstream. Different enzymes have different specificity for their substrate; trypsin, for example, cleaves the peptide bond after
988-419: Is secreted by the stomach, and is activated only in the acidic environment found in stomach. The pancreas secretes the precursors of a number of proteases such as trypsin and chymotrypsin . The zymogen of trypsin is trypsinogen , which is activated by a very specific protease, enterokinase , secreted by the mucosa of the duodenum . The trypsin, once activated, can also cleave other trypsinogens as well as
1040-495: Is synthesized as preproinsulin , which yields proinsulin after the signal peptide has been cleaved. The proinsulin is then cleaved at two positions to yield two polypeptide chains linked by two disulfide bonds . Removal of two C-terminal residues from the B-chain then yields the mature insulin. Protein folding occurs in the single-chain proinsulin form which facilitates formation of the ultimate inter-peptide disulfide bonds, and
1092-817: Is the predominant autoantigen. Recent research indicates that sufferers from neurological diseases like Huntington's and Parkinson's may have unusually high levels of one type of transglutaminase, tissue transglutaminase . It is hypothesized that tissue transglutaminase may be involved in the formation of the protein aggregates that causes Huntington's disease, although it is most likely not required. Mutations in keratinocyte transglutaminase are implicated in lamellar ichthyosis . As of late 2007, 19 structures have been solved for this class of enzymes, with PDB accession codes 1EVU , 1EX0 , 1F13 , 1FIE , 1G0D , 1GGT , 1GGU , 1GGY , 1IU4 , 1KV3 , 1L9M , 1L9N , 1NUD , 1NUF , 1NUG , 1QRK , 1RLE , 1SGX , and 1VJJ . In commercial food processing, transglutaminase
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#17327973067581144-402: Is used to bond proteins together. Examples of foods made using transglutaminase include imitation crabmeat , and fish balls . It is produced by Streptomyces mobaraensis fermentation in commercial quantities ( P81453 ) or extracted from animal blood, and is used in a variety of processes, including the production of processed meat and fish products. Transglutaminase can be used as
1196-459: The peptide bond is cleaved in a self-catalyzed intramolecular reaction . Unlike zymogens , these autoproteolytic proteins participate in a "single turnover" reaction and do not catalyze further reactions post-cleavage. Examples include cleavage of the Asp-Pro bond in a subset of von Willebrand factor type D (VWD) domains and Neisseria meningitidis FrpC self-processing domain, cleavage of
1248-615: The Asn-Pro bond in Salmonella FlhB protein, Yersinia YscU protein, as well as cleavage of the Gly-Ser bond in a subset of sea urchin sperm protein, enterokinase, and agrin (SEA) domains. In some cases, the autoproteolytic cleavage is promoted by conformational strain of the peptide bond. Abnormal proteolytic activity is associated with many diseases. In pancreatitis , leakage of proteases and their premature activation in
1300-486: The TGK genes (5-10%), lies within the cytoplasmic fraction of such cells, allowing for finalization of the cross-linkaging necessary for the full functionality of the cornified cell envelope. A deficiency is associated with ichthyosis lamellaris . Epidermal transglutaminase is the autoantigen, in humans, of dermatitis herpetiformis . A study on the mutation of keratinocyte transglutaminase (TGK) came to conclude that those affected with ichthyosis lamellaris , present
1352-429: The abnormality and reduce bleeding risk. Anti-transglutaminase antibodies are found in celiac disease and may play a role in the small bowel damage in response to dietary gliadin that characterises this condition. In the related condition dermatitis herpetiformis , in which small bowel changes are often found and which responds to dietary exclusion of gliadin-containing wheat products, epidermal transglutaminase
1404-488: The breaking down of connective tissues in the lung. Other proteases and their inhibitors may also be involved in this disease, for example matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Other diseases linked to aberrant proteolysis include muscular dystrophy , degenerative skin disorders, respiratory and gastrointestinal diseases, and malignancy . Protein backbones are very stable in water at neutral pH and room temperature, although
1456-464: The central catalytic domain. The core domain belongs to the papain-like protease superfamily (CA clan) and uses a Cys-His-Asp catalytic triad . Protein 4.2 , also referred to as band 4.2, is a catalytically inactive member of the human transglutaminase family that has a Cys to Ala substitution at the catalytic triad. Bacterial transglutaminases are single-domain proteins with a similarly-folded core. The transglutaminase found in some bacteria runs on
1508-422: The cornified cell envelope protein linkages allow for a structurally fortified, yet flexible (15 nm thick) layer to the place of the cell membrane, acting as a highly insoluble barrier. The expression of the enzyme is most highly exhibited along the biological membrane of these fully formed epithelial cells, preventing the cell from undergoing chemical and or physical damages. A lesser amount of enzymatic activity, of
1560-448: The development of the cornified cell envelope, a defining characteristic of epidermal keratinocytes that have undergone the termination of differentiation. The specific cross linkages formed by keratinocyte transglutaminase are between n^ε-(γ-glutamyl)lysine residues which develop into isopeptide protein-protein linkages that adds to the stabilization of the cornified cell envelope. In terminally differentiated stratified squamous epithelia,
1612-538: The environment for extracellular digestion whereby proteolytic cleavage breaks proteins into smaller peptides and amino acids so that they may be absorbed and used. In animals the food may be processed extracellularly in specialized organs or guts , but in many bacteria the food may be internalized via phagocytosis . Microbial degradation of protein in the environment can be regulated by nutrient availability. For example, limitation for major elements in proteins (carbon, nitrogen, and sulfur) induces proteolytic activity in
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1664-553: The final functional form of protein is termed proprotein , and these proproteins may be first synthesized as preproprotein. For example, albumin is first synthesized as preproalbumin and contains an uncleaved signal peptide. This forms the proalbumin after the signal peptide is cleaved, and a further processing to remove the N-terminal 6-residue propeptide yields the mature form of the protein. The initiating methionine (and, in bacteria, fMet ) may be removed during translation of
1716-546: The fungus Neurospora crassa as well as in of soil organism communities. Proteins in cells are broken into amino acids. This intracellular degradation of protein serves multiple functions: It removes damaged and abnormal proteins and prevents their accumulation. It also serves to regulate cellular processes by removing enzymes and regulatory proteins that are no longer needed. The amino acids may then be reused for protein synthesis. The intracellular degradation of protein may be achieved in two ways—proteolysis in lysosome , or
1768-579: The generation and ineffective removal of peptides that aggregate in cells. Proteases may be regulated by antiproteases or protease inhibitors , and imbalance between proteases and antiproteases can result in diseases, for example, in the destruction of lung tissues in emphysema brought on by smoking tobacco. Smoking is thought to increase the neutrophils and macrophages in the lung which release excessive amount of proteolytic enzymes such as elastase , such that they can no longer be inhibited by serpins such as α 1 -antitrypsin , thereby resulting in
1820-459: The laboratory, and it may also be used in industry, for example in food processing and stain removal. Limited proteolysis of a polypeptide during or after translation in protein synthesis often occurs for many proteins. This may involve removal of the N-terminal methionine , signal peptide , and/or the conversion of an inactive or non-functional protein to an active one. The precursor to
1872-487: The nascent protein. For E. coli , fMet is efficiently removed if the second residue is small and uncharged, but not if the second residue is bulky and charged. In both prokaryotes and eukaryotes , the exposed N-terminal residue may determine the half-life of the protein according to the N-end rule . Proteins that are to be targeted to a particular organelle or for secretion have an N-terminal signal peptide that directs
1924-414: The organism, such as its hormonal state as well as nutritional status. In time of starvation, the rate of protein degradation increases. In human digestion , proteins in food are broken down into smaller peptide chains by digestive enzymes such as pepsin , trypsin , chymotrypsin , and elastase , and into amino acids by various enzymes such as carboxypeptidase , aminopeptidase , and dipeptidase . It
1976-489: The organism, while proteolytic processing of a polypeptide chain after its synthesis may be necessary for the production of an active protein. It is also important in the regulation of some physiological and cellular processes including apoptosis , as well as preventing the accumulation of unwanted or misfolded proteins in cells. Consequently, abnormality in the regulation of proteolysis can cause disease. Proteolysis can also be used as an analytical tool for studying proteins in
2028-467: The pancreas results in the self-digestion of the pancreas . People with diabetes mellitus may have increased lysosomal activity and the degradation of some proteins can increase significantly. Chronic inflammatory diseases such as rheumatoid arthritis may involve the release of lysosomal enzymes into extracellular space that break down surrounding tissues. Abnormal proteolysis may result in many age-related neurological diseases such as Alzheimer 's due to
2080-425: The peptide bond may be easily hydrolyzed, with its half-life dropping to about a minute. Protein may also be broken down without hydrolysis through pyrolysis ; small heterocyclic compounds may start to form upon degradation. Above 500 °C, polycyclic aromatic hydrocarbons may also form, which is of interest in the study of generation of carcinogens in tobacco smoke and cooking at high heat. Proteolysis
2132-461: The peptide bonds in a protein ( acid hydrolysis ). The standard way to hydrolyze a protein or peptide into its constituent amino acids for analysis is to heat it to 105 °C for around 24 hours in 6M hydrochloric acid . However, some proteins are resistant to acid hydrolysis. One well-known example is ribonuclease A , which can be purified by treating crude extracts with hot sulfuric acid so that other proteins become degraded while ribonuclease A
Keratinocyte transglutaminase - Misplaced Pages Continue
2184-417: The precursors of other proteases such as chymotrypsin and carboxypeptidase to activate them. In bacteria, a similar strategy of employing an inactive zymogen or prezymogen is used. Subtilisin , which is produced by Bacillus subtilis , is produced as preprosubtilisin, and is released only if the signal peptide is cleaved and autocatalytic proteolytic activation has occurred. Proteolysis is also involved in
2236-408: The presence of free α-amino group, the negative charge of protein, and the flexibility and stability of the protein. Proteins with larger degrees of intrinsic disorder also tend to have short cellular half-life, with disordered segments having been proposed to facilitate efficient initiation of degradation by the proteasome . The rate of proteolysis may also depend on the physiological state of
2288-448: The protein products of proto-oncogenes, which play central roles in the regulation of cell growth. Cyclins are a group of proteins that activate kinases involved in cell division. The degradation of cyclins is the key step that governs the exit from mitosis and progress into the next cell cycle . Cyclins accumulate in the course the cell cycle, then abruptly disappear just before the anaphase of mitosis. The cyclins are removed via
2340-546: The protein to its final destination. This signal peptide is removed by proteolysis after their transport through a membrane . Some proteins and most eukaryotic polypeptide hormones are synthesized as a large precursor polypeptide known as a polyprotein that requires proteolytic cleavage into individual smaller polypeptide chains. The polyprotein pro-opiomelanocortin (POMC) contains many polypeptide hormones. The cleavage pattern of POMC, however, may vary between different tissues, yielding different sets of polypeptide hormones from
2392-475: The rate of hydrolysis of different peptide bonds can vary. The half life of a peptide bond under normal conditions can range from 7 years to 350 years, even higher for peptides protected by modified terminus or within the protein interior. The rate of hydrolysis however can be significantly increased by extremes of pH and heat. Spontaneous cleavage of proteins may also involve catalysis by zinc on serine and threonine. Strong mineral acids can readily hydrolyse
2444-449: The regulation of many cellular processes by activating or deactivating enzymes, transcription factors, and receptors, for example in the biosynthesis of cholesterol, or the mediation of thrombin signalling through protease-activated receptors . Some enzymes at important metabolic control points such as ornithine decarboxylase is regulated entirely by its rate of synthesis and its rate of degradation. Other rapidly degraded proteins include
2496-458: The same polyprotein. Many viruses also produce their proteins initially as a single polypeptide chain that were translated from a polycistronic mRNA. This polypeptide is subsequently cleaved into individual polypeptide chains. Common names for the polyprotein include gag ( group-specific antigen ) in retroviruses and ORF1ab in Nidovirales . The latter name refers to the fact that
2548-463: The subjects of the study. Such mutations were of the compound heterozygous or homozygous variety, which leads to the expression of lamellar ichthyosis as a result of abnormal cross-linkaging of the cornified cell envelope. Transglutaminase Transglutaminases are enzymes that in nature primarily catalyze the formation of an isopeptide bond between γ- carboxamide groups ( -(C=O)NH 2 ) of glutamine residue side chains and
2600-445: The ultimate intra-peptide disulfide bond, found in the native structure of insulin. Proteases in particular are synthesized in the inactive form so that they may be safely stored in cells, and ready for release in sufficient quantity when required. This is to ensure that the protease is activated only in the correct location or context, as inappropriate activation of these proteases can be very destructive for an organism. Proteolysis of
2652-439: The zymogen yields an active protein; for example, when trypsinogen is cleaved to form trypsin , a slight rearrangement of the protein structure that completes the active site of the protease occurs, thereby activating the protein. Proteolysis can, therefore, be a method of regulating biological processes by turning inactive proteins into active ones. A good example is the blood clotting cascade whereby an initial event triggers
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#17327973067582704-439: The ε- amino groups ( -NH 2 ) of lysine residue side chains with subsequent release of ammonia ( NH 3 ). Lysine and glutamine residues must be bound to a peptide or a protein so that this cross-linking (between separate molecules) or intramolecular (within the same molecule) reaction can happen. Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation ( proteolysis ). The reaction
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