Biology:Transglutaminase

Short description: Class of enzymes capable of forming isopeptide bonds in certain regions of proteins

Transglutaminase
Transglutaminase example: coagulation factor XIII from human blood. PDB code: 1EVU.
Identifiers
EC number	2.3.2.13
CAS number	80146-85-6
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

Transglutaminases are enzymes that in nature primarily catalyze the formation of an isopeptide bond between γ-carboxamide groups ( -(C=O)NH₂ ) of glutamine residue side chains and the ε-amino groups ( -NH₂ ) of lysine residue side chains with subsequent release of ammonia ( NH₃ ). 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 is

Gln-(C=O)NH₂ + NH₂-Lys → Gln-(C=O)NH-Lys + NH₃

Transglutaminases can also join a primary amine ( RNH₂ ) to the side chain carboxyamide group of a protein/peptide bound glutamine residue thus forming an isopeptide bond

Gln-(C=O)NH₂ + RNH₂ → Gln-(C=O)NHR + NH₃

These enzymes can also deamidate glutamine residues to glutamic acid residues in the presence of water

Gln-(C=O)NH₂ + H₂O → Gln-COOH + NH₃

Transglutaminase isolated from Streptomyces mobaraensis -bacteria for example, is a calcium-independent enzyme. Mammalian transglutaminases among other transglutaminases require Ca²⁺ ions as a cofactor.

Transglutaminases were first described in 1959. The exact biochemical activity of transglutaminases was discovered in blood coagulation protein factor XIII in 1968.

Examples

The upper reaction shows how a transaminase combines with a glutamine residue, releasing ammonia, and then the combination reacts with the amine group of a lysine residue of another protein, setting the enzyme free again.

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 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.

Name	Gene	Activity	Chromosome	OMIM
Factor XIII (fibrin-stabilizing factor) chain A	F13A1	coagulation	6p25-p24	Online Mendelian Inheritance in Man (OMIM) 134570
Keratinocyte transglutaminase	TGM1	skin	14q11.2	Online Mendelian Inheritance in Man (OMIM) 190195
Tissue transglutaminase	TGM2	ubiquitous	20q11.2-q12	Online Mendelian Inheritance in Man (OMIM) 190196
Epidermal transglutaminase	TGM3	skin	20q12	Online Mendelian Inheritance in Man (OMIM) 600238
Prostate transglutaminase	TGM4	prostate	3p22-p21.33	Online Mendelian Inheritance in Man (OMIM) 600585
TGM X	TGM5	skin	15q15.2	Online Mendelian Inheritance in Man (OMIM) 603805
TGM Y	TGM6	nerves, CNS	20q11-15	Online Mendelian Inheritance in Man (OMIM) 613900
TGM Z	TGM7	testis, lung	15q15.2	Online Mendelian Inheritance in Man (OMIM) 606776
Protein 4.2	EPB42	erythrocytes, bone marrow, spleen	15q15.2	Online Mendelian Inheritance in Man (OMIM) 177070

Bacterial transglutaminases are single-domain proteins with a similarly-folded core. The transglutaminase found in some bacteria runs on a Cys-Asp diad.

Transglutaminase, N-terminal, Ig E-set-like Identifiers Symbol Transglut_N Pfam PF00868 InterPro IPR001102 CATH 1ex0A01 SCOP2 d1ex0a1 / SCOPe / SUPFAM Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Transglutaminase-like, core Identifiers Symbol Transglut_core Pfam PF01841 InterPro IPR002931 SMART SM00460 PROSITE PS00547 CATH 1ex0A02 SCOP2 d1ex0a4 / SCOPe / SUPFAM Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Transglutaminase, C-terminal, Ig-like Identifiers Symbol Transglut_C Pfam PF00927 InterPro IPR008958 CATH 1ex0A03 SCOP2 d1ex0a2 / SCOPe / SUPFAM Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Transglutaminase, bacterial Identifiers Symbol Transglut_prok Pfam PF09017 InterPro IPR015107 CATH 3iu0 SCOP2 1iu4 / SCOPe / SUPFAM Available protein structures: Pfam   structures / ECOD   PDB RCSB PDB; PDBe; PDBj PDBsum structure summary

Biological role

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.

Role in disease

Deficiency of factor XIII (a rare genetic condition) predisposes to hemorrhage; concentrated enzyme can be used to correct 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 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.

Structural studies

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.

Industrial and culinary applications

Three bistro tenders being joined together with transglutaminase "meat glue". They will set overnight before being unwrapped, sliced into portions, cooked, and served.

Transglutaminase treated chicken terrine.

In commercial food processing, transglutaminase 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 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.

Molecular gastronomy

Transglutaminase 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 a "pasta" made from over 95% shrimp thanks to transglutaminase.

Synonyms

• protein-glutamine gamma-glutamyltransferase (systematic)
• fibrinoligase
• glutaminylpeptide gamma-glutamyltransferase
• protein-glutamine:amine gamma-glutamyltransferase
• R-glutaminyl-peptide:amine gamma-glutamyl transferase

See also

• Boneless Fish
• Surimi
• Bromelain
• Papain
• Ficain

Further reading

• "Recent advances in microbial transglutaminase biosynthesis and its application in the food industry". Trends in Food Science & Technology. 2021. https://www.sciencedirect.com/science/article/pii/S0958694623001206?via%3Dihub. Retrieved 31 August 2023. 
• Fesus, Laszlo; Hitomi, Kiyotaka; Kojima, Soichi (2015). Transglutaminases: Multiple Functional Modifiers and Targets for New Drug Discovery. Springer Japan. ISBN 978-4-431-55823-1. 
• Nuijens, Timo; Schmidt, Marcel (2019). Enzyme-mediated ligation methods. Humana, New York, NY. ISBN 978-1-4939-9545-5. 
• Kuddus, Mohammed (2018). Enzymes in food technology : improvements and innovations. Springer, Singapore. ISBN 978-981-13-1932-7. 
• "Industry defends ingredient critics deride as "meat glue"". Chicago Tribune. 11 May 2012. http://articles.chicagotribune.com/2012-05-11/news/sns-rt-us-usa-food-meat-gluebre84a00x-20120510_1_ammonia-treated-beef-ground-beef-beef-products. 
• "Properties of yoghurt treated with microbial transglutaminase and exopolysaccharides". International Dairy Journal. 2023. https://www.sciencedirect.com/science/article/pii/S0958694623001206?via%3Dihub. Retrieved 31 August 2023. 
• U.S. Patent 5,156,956 – A transglutaminase catalyzing an acyl transfer reaction of a Γ-carboxyamide group of a glutamine residue in a peptide or protein chain in the absence of Ca²⁺