transglutaminase 2 | 2.3.2.13 Transglutaminases | IUPHAR Guide to IMMUNOPHARMACOLOGY

transglutaminase 2

Target id: 3015

Nomenclature: transglutaminase 2

Family: 2.3.2.13 Transglutaminases

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

   GtoImmuPdb view: ON :     transglutaminase 2 has curated GtoImmuPdb data

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 687 20q11.23 TGM2 transglutaminase 2
Mouse - 686 2 H1; 2 78.72 cM Tgm2 transglutaminase 2, C polypeptide
Rat - 686 3q42 Tgm2 transglutaminase 2
Gene and Protein Information Comments
Multiple transcript variants encoding different isoforms have been found for the human TGM2 gene.
Previous and Unofficial Names
C polypeptide, protein-glutamine-gamma-glutamyltransferase | TGC | tissue transglutaminase | TGase2
Database Links
BRENDA
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Enzyme Reaction
EC Number: 2.3.2.13
Description Reaction Reference
A protein-L-glutamine + a protein-L-lysine <=> a protein with an N6-(gamma-glutamyl)-L-lysine cross-link + NH3

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Affinity Units Reference
JAK3 inhibitor IV Hs Inhibition 8.0 pIC50 7
pIC50 8.0 (IC50 1x10-8 M) [7]
Description: In the absence of DTT.
ERW1041E Hs Inhibition 5.8 pIC50 2
pIC50 5.8 (IC50 1.6x10-6 M) [2]
Description: Inhibition of enzyme activity in vitro.
Immunopharmacology Comments
TGM2 upregulation by amyloid β (Aβ)1-42 in THP-1 monocytes increases pro-inflammatory mediators, including IL-1β and IL-6. A transglutaminase inhibitor can blunt this activation, suggesting that TGM2 up-regulation is involved in the pro-inflammatory effect of Aβ1-42 on monocytes [3]. UCB Biopharma have a TGM2 antibody-based candidate (UCB7858; proposed INN zampilimab) for the treatment of auto-inflammatory disorders in early stage clinical testing. UCB7858 has completed Phase 1 evaluation in healthy subjects (see NCT02879877).
Physiological Consequences of Altering Gene Expression Comments
Evidence of chronic expression of TGM2 and the contribution made by dysregulated TGM2 pathways to the aggressive phenotype in breast cancer is reviewed by Agnihotri et al. (2013) [1].
General Comments
Transglutaminase 2 (TGM2) is an inducible enzyme that is expressed in almost all cell types, and although it is predominantly a cytosolic protein, it can be detected intracellularly, on the cell surface and as a secreted protein within the extracellular matrix [10]. It is particularly abundant in endothelial cells, fibroblasts, osteoblasts, monocytes/macrophages, and smooth muscle cells. In addition to its transglutaminase activity, TGM2 can act as a G protein, kinase, protein disulfide isomerase, and as a cell surface adhesion mediator (serving as a co-receptor for integrin β1 and β3 integrins) [4-5,9]. It is involved in an extensive variety of cellular processes including differentiation, apoptosis, inflammation, cell migration, and wound healing, and has been implicated in a range of human diseases including inflammation, cancer, fibrosis, cardiovascular and neurodegenerative diseases [13], and has been identified as the autoantigen implicated in celiac disease [6,8,11]. TGM2 modulation is therefore considered to offer therapeutic potential across this wide range of transglutaminase-linked, pathological states [12].

References

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1. Agnihotri N, Kumar S, Mehta K. (2013) Tissue transglutaminase as a central mediator in inflammation-induced progression of breast cancer. Breast Cancer Res., 15 (1): 202. [PMID:23673317]

2. Chrobok NL, Bol JGJM, Jongenelen CA, Brevé JJP, El Alaoui S, Wilhelmus MMM, Drukarch B, van Dam AM. (2018) Characterization of Transglutaminase 2 activity inhibitors in monocytes in vitro and their effect in a mouse model for multiple sclerosis. PLoS ONE, 13 (4): e0196433 eCollection 2018. DOI: 10.1371/journal.pone.0196433 [PMID:29689097]

3. Currò M, Gangemi C, Giunta ML, Ferlazzo N, Navarra M, Ientile R, Caccamo D. (2017) Transglutaminase 2 is involved in amyloid-beta1-42-induced pro-inflammatory activation via AP1/JNK signalling pathways in THP-1 monocytes. Amino Acids, 49 (3): 659-669. [PMID:27864692]

4. Fesus L, Piacentini M. (2002) Transglutaminase 2: an enigmatic enzyme with diverse functions. Trends Biochem. Sci., 27 (10): 534-9. [PMID:12368090]

5. Gundemir S, Colak G, Tucholski J, Johnson GV. (2012) Transglutaminase 2: a molecular Swiss army knife. Biochim. Biophys. Acta, 1823 (2): 406-19. [PMID:22015769]

6. Jabri B, Chen X, Sollid LM. (2014) How T cells taste gluten in celiac disease. Nat. Struct. Mol. Biol., 21 (5): 429-31. [PMID:24777059]

7. Lai TS, Liu Y, Tucker T, Daniel KR, Sane DC, Toone E, Burke JR, Strittmatter WJ, Greenberg CS. (2008) Identification of chemical inhibitors to human tissue transglutaminase by screening existing drug libraries. Chem. Biol., 15 (9): 969-78. [PMID:18804034]

8. Maiuri L, Ciacci C, Ricciardelli I, Vacca L, Raia V, Rispo A, Griffin M, Issekutz T, Quaratino S, Londei M. (2005) Unexpected role of surface transglutaminase type II in celiac disease. Gastroenterology, 129 (5): 1400-13. [PMID:16285941]

9. Nurminskaya MV, Belkin AM. (2012) Cellular functions of tissue transglutaminase. Int Rev Cell Mol Biol, 294: 1-97. [PMID:22364871]

10. Park D, Choi SS, Ha KS. (2010) Transglutaminase 2: a multi-functional protein in multiple subcellular compartments. Amino Acids, 39 (3): 619-31. [PMID:20148342]

11. Sollid LM, Jabri B. (2011) Celiac disease and transglutaminase 2: a model for posttranslational modification of antigens and HLA association in the pathogenesis of autoimmune disorders. Curr. Opin. Immunol., 23 (6): 732-8. [PMID:21917438]

12. Song M, Hwang H, Im CY, Kim SY. (2017) Recent Progress in the Development of Transglutaminase 2 (TGase2) Inhibitors. J. Med. Chem., 60 (2): 554-567. [PMID:28122456]

13. Szondy Z, Korponay-Szabó I, Király R, Sarang Z, Tsay GJ. (2017) Transglutaminase 2 in human diseases. Biomedicine (Taipei), 7 (3): 15. [PMID:28840829]

How to cite this page

2.3.2.13 Transglutaminases: transglutaminase 2. Last modified on 17/08/2018. Accessed on 19/10/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetoimmunopharmacology.org/GRAC/ObjectDisplayForward?objectId=3015.