Transglutaminase

{{Short description|Class of enzymes capable of forming isopeptide bonds in certain regions of proteins}} {{Distinguish|Glutaminase}} {{Use dmy dates|date=March 2020}} {{Infobox enzyme | name = Transglutaminase | image = Coagulation factor XIII 1EVU.png | caption = Transglutaminase example: coagulation factor XIII from human blood. PDB code: 1EVU. | EC_number = 2.3.2.13 | CAS_number = 80146-85-6 | GO_code = | Name = | width = }} '''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.<ref name=":0">{{cite journal |vauthors=DeJong GA, Koppelman SJ |date=2002 |title=Transglutaminase Catalyzed Reactions: Impact on Food Applications |journal=Journal of Food Science |volume=67 |issue=8 |pages=2798–2806 |doi=10.1111/j.1365-2621.2002.tb08819.x}}</ref> Bonds formed by transglutaminase exhibit high resistance to proteolytic degradation (proteolysis).<ref name="Griffin"/> The reaction is<ref name=":0"/> :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<ref name=":0"/> :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<ref name=":0"/> :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.<ref name=":0"/>

Transglutaminases were first described in 1959.<ref>{{Cite journal |vauthors=Clarke DD, Mycek MJ, Neidle A, Waelsch H |title=The incorporation of amines into proteins |journal=Arch Biochem Biophys |year=1959 |volume=79 |pages=338–354 |doi=10.1016/0003-9861(59)90413-8}} </ref> The exact biochemical activity of transglutaminases was discovered in blood coagulation protein factor XIII in 1968.<ref>{{cite journal |vauthors=Pisano JJ, Finlayson JS, Peyton MP |title=[Cross-link in fibrin polymerized by factor 13: epsilon-(gamma-glutamyl)lysine] |journal=Science |volume=160 |issue=3830 |pages=892–3 |date=May 1968 |bibcode=1968Sci...160..892P |pmid=4967475 |doi=10.1126/science.160.3830.892 |s2cid=95459438}}</ref>

==Examples== [[File:Transamidation and deamidation mechanisms of tissue transglutaminase.jpg|thumb|right|alt=reaction mechanism of tTG|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,<ref>{{cite journal |vauthors=Grenard P, Bates MK, Aeschlimann D |title=Evolution of transglutaminase genes: identification of a transglutaminase gene cluster on human chromosome 15q15. Structure of the gene encoding transglutaminase X and a novel gene family member, transglutaminase Z |journal=The Journal of Biological Chemistry |volume=276 |issue=35 |pages=33066–78 |date=August 2001 |pmid=11390390 |doi=10.1074/jbc.M102553200 |doi-access=free}}</ref> 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.<ref name=Griffin>{{cite journal |vauthors=Griffin M, Casadio R, Bergamini CM |title=Transglutaminases: nature's biological glues |journal=The Biochemical Journal |volume=368 |issue=Pt 2 |pages=377–96 |date=December 2002 |pmid=12366374 |doi=10.1042/BJ20021234 |pmc=1223021}}</ref> 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.<ref>{{cite journal |vauthors=Eckert RL, Kaartinen MT, Nurminskaya M, Belkin AM, Colak G, Johnson GV, Mehta K |title=Transglutaminase regulation of cell function |journal=Physiological Reviews |volume=94 |issue=2 |pages=383–417 |date=April 2014 |pmid=24692352 |doi=10.1152/physrev.00019.2013 |pmc=4044299}}</ref>

{| border="1" class=wikitable ! Name !! Gene !! Activity !! Chromosome !! OMIM |- | Factor XIII (fibrin-stabilizing factor) chain A || F13A1 || coagulation || 6p25-p24 || {{OMIM|134570||none}} |- | Keratinocyte transglutaminase || TGM1 || skin || 14q11.2 || {{OMIM|190195||none}} |- | Tissue transglutaminase || TGM2 || ubiquitous || 20q11.2-q12 || {{OMIM|190196||none}} |- | Epidermal transglutaminase || TGM3 || skin || 20q12 || {{OMIM|600238||none}} |- | Prostate transglutaminase || TGM4 || prostate || 3p22-p21.33 || {{OMIM|600585||none}} |- | TGM X || TGM5<ref>{{cite journal |vauthors=Aeschlimann D, Koeller MK, Allen-Hoffmann BL, Mosher DF |title=Isolation of a cDNA encoding a novel member of the transglutaminase gene family from human keratinocytes. Detection and identification of transglutaminase gene products based on reverse transcription-polymerase chain reaction with degenerate primers |journal=The Journal of Biological Chemistry |volume=273 |issue=6 |pages=3452–60 |date=February 1998 |df=dmy-all |pmid=9452468 |doi=10.1074/jbc.273.6.3452 |doi-access=free}}</ref> || skin || 15q15.2 || {{OMIM|603805||none}} |- | TGM Y || TGM6 || nerves, CNS || 20q11-15 || {{OMIM|613900||none}} |- | TGM Z || TGM7 || testis, lung || 15q15.2 || {{OMIM|606776||none}} |- | Protein 4.2 || EPB42 || erythrocytes, bone marrow, spleen || 15q15.2 || {{OMIM|177070||none}} |}

Bacterial transglutaminases are single-domain proteins with a similarly-folded core. The transglutaminase found in some bacteria runs on a Cys-Asp diad.<ref>{{cite journal |vauthors=Kashiwagi T, Yokoyama K, Ishikawa K, Ono K, Ejima D, Matsui H, Suzuki E |title=Crystal structure of microbial transglutaminase from Streptoverticillium mobaraense |journal=The Journal of Biological Chemistry |volume=277 |issue=46 |pages=44252–60 |date=November 2002 |pmid=12221081 |doi=10.1074/jbc.M203933200 |doi-access=free}}</ref> <div style="display:flex;flex-wrap:wrap;"> {{Infobox protein family |Name=Transglutaminase, N-terminal, Ig E-set-like |Pfam=PF00868|Symbol=Transglut_N |InterPro=IPR001102 |CATH=1ex0A01|SCOP=d1ex0a1 }} {{Infobox protein family |Name=Transglutaminase-like, core |Pfam=PF01841|Symbol=Transglut_core |SMART=SM00460 |PROSITE=PS00547 |InterPro=IPR002931 |CATH=1ex0A02|SCOP=d1ex0a4 }} {{Infobox protein family |Name=Transglutaminase, C-terminal, Ig-like |Pfam=PF00927|Symbol=Transglut_C |InterPro=IPR008958 |CATH=1ex0A03|SCOP=d1ex0a2 }} {{Infobox protein family |Name=Transglutaminase, bacterial |Pfam=PF09017|Symbol=Transglut_prok |InterPro=IPR015107 |CATH=3iu0|SCOP=1iu4 }} </div>

==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.<ref name="Griffin"/>

==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.<ref name=Griffin/>

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.<ref name=Griffin/> 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.<ref>{{cite journal |vauthors=Sárdy M, Kárpáti S, Merkl B, Paulsson M, Smyth N |title=Epidermal transglutaminase (TGase 3) is the autoantigen of dermatitis herpetiformis |journal=The Journal of Experimental Medicine |volume=195 |issue=6 |pages=747–57 |date=March 2002 |df=dmy-all |pmid=11901200 |doi=10.1084/jem.20011299 |pmc=2193738}}</ref>

Recent research indicates that sufferers from neurological diseases like Huntington's<ref name="Huntington">{{cite journal |vauthors=Karpuj MV, Becher MW, Steinman L |title=Evidence for a role for transglutaminase in Huntington's disease and the potential therapeutic implications |journal=Neurochemistry International |volume=40 |issue=1 |pages=31–6 |date=January 2002 |pmid=11738470 |doi=10.1016/S0197-0186(01)00060-2 |s2cid=40198925}}</ref> and Parkinson's<ref name="Parkinson's">{{cite journal |vauthors=Vermes I, Steur EN, Jirikowski GF, Haanen C |title=Elevated concentration of cerebrospinal fluid tissue transglutaminase in Parkinson's disease indicating apoptosis |journal=Movement Disorders |volume=19 |issue=10 |pages=1252–4 |date=October 2004 |pmid=15368613 |doi=10.1002/mds.20197 |doi-access=free |s2cid=102503}}</ref> 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.<ref name=Griffin/><ref name="Lesort">{{cite journal |vauthors=Lesort M, Chun W, Tucholski J, Johnson GV |title=Does tissue transglutaminase play a role in Huntington's disease? |journal=Neurochemistry International |volume=40 |issue=1 |pages=37–52 |date=January 2002 |pmid=11738471 |doi=10.1016/S0197-0186(01)00059-6 |s2cid=7983848}}</ref>

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 {{PDB link|1EVU}}, {{PDB link|1EX0}}, {{PDB link|1F13}}, {{PDB link|1FIE}}, {{PDB link|1G0D}}, {{PDB link|1GGT}}, {{PDB link|1GGU}}, {{PDB link|1GGY}}, {{PDB link|1IU4}}, {{PDB link|1KV3}}, {{PDB link|1L9M}}, {{PDB link|1L9N}}, {{PDB link|1NUD}}, {{PDB link|1NUF}}, {{PDB link|1NUG}}, {{PDB link|1QRK}}, {{PDB link|1RLE}}, {{PDB link|1SGX}}, and {{PDB link|1VJJ}}.

==Industrial and culinary applications== thumb|right|Three bistro tenders being joined together with transglutaminase "meat glue". They will set overnight before being unwrapped, sliced into portions, cooked, and served. [[File:ChickenSkinCrustedTerrine (8302655857).jpg|thumb|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 ({{UniProt|P81453}}) or extracted from animal blood,<ref>{{cite news |last=Köhler |first=Wim |name-list-style=vanc |title=Gelijmde slavink |language=nl |publisher=NRC Handelsblad |date=2008-08-22 |df=dmy-all |url=https://www.nrc.nl/nieuws/2008/08/16/gelijmde-slavink-11589851-a1086306 |access-date=2024-07-06 |url-status=live |archive-url=https://web.archive.org/web/20090220132207/http://www.nrc.nl/achtergrond/article1960242.ece/Gelijmde_slavink |archive-date=20 February 2009 }}</ref> 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.<ref>{{cite journal |vauthors=Yokoyama K, Nio N, Kikuchi Y |title=Properties and applications of microbial transglutaminase |journal=Applied Microbiology and Biotechnology |volume=64 |issue=4 |pages=447–54 |date=May 2004 |pmid=14740191 |doi=10.1007/s00253-003-1539-5 |s2cid=19068193}}</ref>

Thrombin–fibrinogen "meat glue" from bovine and porcine sources was banned throughout the European Union as a food additive in 2010.<ref>{{cite web |title=EU Bans 'Meat Glue' - Food Safety News |date=24 May 2010 |website=foodsafetynews.com |url=https://www.foodsafetynews.com/2010/05/eu-bans-meat-glue/ |access-date=6 May 2018 |url-status=live |archive-url=https://web.archive.org/web/20180405025014/http://www.foodsafetynews.com/2010/05/eu-bans-meat-glue/#.WsTo0TDTVyU |archive-date=5 April 2018}}</ref> 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.<ref>{{cite news |last=Jon |first=Bonné |name-list-style=vanc |title=Noodles, reinvented |work=NBC News |date=2005-02-11 |url=https://www.nbcnews.com/id/wbna6915287 |access-date=2008-04-02 }}</ref>

==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 * Bromelain * Ficain * Papain * Surimi

==References== {{Reflist}}

== Further reading == {{Refbegin}} * {{cite journal |title=Recent advances in microbial transglutaminase biosynthesis and its application in the food industry |journal=Trends in Food Science & Technology |date=2021 |vauthors=Akbari et al. |doi=10.1016/j.idairyj.2023.105701 |url=https://www.sciencedirect.com/science/article/abs/pii/S0958694623001206 |access-date=31 August 2023|url-access=subscription }} * {{cite book |last1=Fesus |first1=Laszlo |last2=Hitomi |first2=Kiyotaka |last3=Kojima |first3=Soichi |name-list-style=vanc |title=Transglutaminases: Multiple Functional Modifiers and Targets for New Drug Discovery |date=2015 |publisher=Springer Japan |isbn=978-4-431-55823-1}} * {{cite book |last1=Nuijens |first1=Timo |last2=Schmidt |first2=Marcel |name-list-style=vanc |title=Enzyme-mediated ligation methods |date=2019 |publisher=Humana, New York, NY |isbn=978-1-4939-9545-5}} * {{cite book |last1=Kuddus |first1=Mohammed |name-list-style=vanc |title=Enzymes in food technology : improvements and innovations |date=2018 |publisher=Springer, Singapore |isbn=978-981-13-1932-7}} * {{cite news |title=Industry defends ingredient critics deride as "meat glue" |newspaper=Chicago Tribune |date=11 May 2012 |vauthors=Kelleher JB |url=https://www.chicagotribune.com/2012/05/11/industry-defends-ingredient-critics-deride-as-meat-glue-2/ |access-date=20 July 2012}} * {{cite journal |title=Properties of yoghurt treated with microbial transglutaminase and exopolysaccharides |journal=International Dairy Journal |date=2023 |vauthors=Marhons et al. |volume=144 |article-number=105701 |doi=10.1016/j.idairyj.2023.105701 |url=https://www.sciencedirect.com/science/article/abs/pii/S0958694623001206 |access-date=31 August 2023|url-access=subscription }} *{{US patent|5156956}}{{spaced en dash}} 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+ {{Refend}}

Category:Autoantigens Category:Calcium enzymes * Category:Enzymes of known structure Category:Food additives