View source for 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 [[enzyme]]s that in nature primarily [[catalyze]] the formation of an [[isopeptide bond]] between γ-[[carboxamide]] groups (&nbsp;-(C=O)NH<sub>2</sub>&nbsp;) of [[glutamine]] residue [[side chain]]s and the ε-[[amino group]]s ( -NH<sub>2</sub> ) of [[lysine]] residue side chains with subsequent release of [[ammonia]] (&nbsp;NH<sub>3</sub>&nbsp;). Lysine and glutamine residues must be bound to a [[peptide]] or a [[protein]] so that this [[cross-link]]ing (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"/>
:[[glutamine|Gln-(C=O)NH<sub>2</sub>]] + [[lysine|NH<sub>2</sub>-Lys]] → Gln-(C=O)NH-Lys + NH<sub>3</sub>
Transglutaminases can also join a [[primary amine]] (&nbsp;RNH<sub>2</sub>&nbsp;) to the side chain carboxyamide group of a protein/peptide bound glutamine residue thus forming an isopeptide bond<ref name=":0"/>
:Gln-(C=O)NH<sub>2</sub> + RNH<sub>2</sub> → Gln-(C=O)NHR + NH<sub>3</sub>

These enzymes can also [[deamidation|deamidate]] glutamine residues to [[glutamic acid]] residues in the presence of water<ref name=":0"/>
:Gln-(C=O)NH<sub>2</sub> + H<sub>2</sub>O → [[Glutamic acid|Gln-COOH]] + NH<sub>3</sub>
Transglutaminase isolated from ''[[Streptomyces mobaraensis]]'' -[[bacteria]] for example, is a [[calcium]]-independent enzyme. [[Mammalian]] transglutaminases among other transglutaminases require Ca<sup>2+</sup> ions as a [[cofactor (biochemistry)|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}} <!--not indexed on PubMed--></ref> The exact biochemical activity of transglutaminases was discovered in [[coagulation|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]] !! [[Mendelian Inheritance in Man|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 clot]]s (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 disease|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 disease|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 [[tertiary structure|structures]] have been solved for this class of enzymes, with [[Protein Data Bank|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==
[[File:GluedBistroTenders.jpg|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 (food)|terrine]].]]
In commercial food processing, transglutaminase is used to bond [[protein]]s together. Examples of foods made using transglutaminase include [[imitation crabmeat]], and [[fish ball]]s. It is produced by ''[[Streptomyces mobaraensis]]'' [[industrial fermentation|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]]&ndash;[[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 Ca<sup>2+</sup>
{{Refend}}

{{Acyltransferases}}
{{Enzymes}}
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[[Category:Autoantigens]]
[[Category:Calcium enzymes]]
[[Category:EC 2.3.2|*]]
[[Category:Enzymes of known structure]]
[[Category:Food additives]]