transglutaminase 2

Target id: 3015

Nomenclature: transglutaminase 2

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	-	687	20q11.23	TGM2	transglutaminase 2
Mouse	-	686	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
transglutaminase 2, C polypeptide \| C polypeptide, protein-glutamine-gamma-glutamyltransferase \| TGC \| tissue transglutaminase \| TGase2

Previous and Unofficial Names

transglutaminase 2, C polypeptide | C polypeptide, protein-glutamine-gamma-glutamyltransferase | TGC | tissue transglutaminase | TGase2

Database Links
Alphafold	P21980 (Hs), P21981 (Mm)
BRENDA	2.3.2.13
ChEMBL Target	CHEMBL2730 (Hs), CHEMBL2079853 (Mm)
Ensembl Gene	ENSG00000198959 (Hs), ENSMUSG00000037820 (Mm), ENSRNOG00000012956 (Rn)
Entrez Gene	7052 (Hs), 21817 (Mm), 56083 (Rn)
Human Protein Atlas	ENSG00000198959 (Hs)
KEGG Enzyme	2.3.2.13
KEGG Gene	hsa:7052 (Hs), mmu:21817 (Mm), rno:56083 (Rn)
OMIM	190196 (Hs)
Pharos	P21980 (Hs)
RefSeq Nucleotide	NM_004613 (Hs), NM_009373 (Mm), NM_019386 (Rn)
RefSeq Protein	NP_004604 (Hs), NP_033399 (Mm), NP_062259 (Rn)
UniProtKB	P21980 (Hs), P21981 (Mm)
Wikipedia	TGM2 (Hs)

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

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Ligand		Sp.	Action	Value	Parameter	Reference
compound 11 [PMID: 37449845]		Hs	Inhibition	4.2	pK_d	15
⤷	pK_d 4.2 (K_d 6.89x10^-5 M) [15]
JAK3 inhibitor IV		Hs	Inhibition	8.0	pIC₅₀	8
⤷	pIC₅₀ 8.0 (IC₅₀ 1x10^-8 M) [8] Description: In the absence of DTT.
ZED1227		Hs	Inhibition	7.3	pIC₅₀	2
⤷	pIC₅₀ 7.3 (IC₅₀ 5.3x10^-8 M) [2]
ERW1041E		Hs	Inhibition	5.8	pIC₅₀	3
⤷	pIC₅₀ 5.8 (IC₅₀ 1.6x10^-6 M) [3] 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 Aβ_1-42 on monocytes [4]. UCB Biopharma have an anti-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). Evidence also indicates that TG2-regulated pathways contribute to inflammation-induced progression of, and aggression of breast cancer [1]. UCB7858 blockade of TGM2 may also offer value in this indication as an immuno-oncology agent.

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 Aβ_1-42 on monocytes [4]. UCB Biopharma have an anti-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). Evidence also indicates that TG2-regulated pathways contribute to inflammation-induced progression of, and aggression of breast cancer [1]. UCB7858 blockade of TGM2 may also offer value in this indication as an immuno-oncology agent.

Immuno Process Associations

Immuno Process:

Inflammation

Immuno Process:

Immune regulation

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 [11]. 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) [5-6,10]. 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 [14], and has been identified as the autoantigen implicated in celiac disease [7,9,12]. TGM2 modulation is therefore considered to offer therapeutic potential across this wide range of transglutaminase-linked, pathological states [13].

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 [11]. 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) [5-6,10]. 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 [14], and has been identified as the autoantigen implicated in celiac disease [7,9,12]. TGM2 modulation is therefore considered to offer therapeutic potential across this wide range of transglutaminase-linked, pathological states [13].

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. Büchold C, Hils M, Gerlach U, Weber J, Pelzer C, Heil A, Aeschlimann D, Pasternack R. (2022) Features of ZED1227: The First-In-Class Tissue Transglutaminase Inhibitor Undergoing Clinical Evaluation for the Treatment of Celiac Disease. Cells, 11 (10). DOI: 10.3390/cells11101667 [PMID:35626704]

3. 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]

4. Currò M, Gangemi C, Giunta ML, Ferlazzo N, Navarra M, Ientile R, Caccamo D. (2017) Transglutaminase 2 is involved in amyloid-beta_1-42-induced pro-inflammatory activation via AP1/JNK signalling pathways in THP-1 monocytes. Amino Acids, 49 (3): 659-669. [PMID:27864692]

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

6. 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]

7. 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]

8. 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]

9. 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]

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

11. 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]

12. 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]

13. 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]

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

15. Valdivia A, Vagadia PP, Guo G, O'Brien E, Matei D, Schiltz GE. (2023) Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2). J Med Chem, 66 (14): 9445-9465. [PMID:37449845]

How to cite this page

2.3.2.13 Transglutaminases: transglutaminase 2. Last modified on 18/07/2023. Accessed on 16/04/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetomalariapharmacology.org/GRAC/ObjectDisplayForward?objectId=3015.

transglutaminase 2

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References

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