PET imaging of transglutaminase type 2

Transglutaminases

Transglutaminase (Tgase) family contains eight enzymes, TG1-TG7 and Factor XIII. Transglutaminases can cross-link proteins by forming intermolecular isopeptide bonds between the side chains of glutamine and lysine residues, and participate in post-translational modification of proteins.

Transglutaminase type 2 (TG2, Tgase2) is the most ubiquitously expressed member of the Tgase family, but most tissues express also other TG types. TG2 is also found in erythrocytes.

Transglutaminase type 2

TG2 is mainly expressed intracellularly. TG2 has several functions: it assists in cell migration and adhesion, and during cell apoptosis it cross-links intracellular components, preventing the leakage of cellular debris. Extracellular TG2 (at cell surface) participates in deposition and stabilization of the extracellular matrix (ECM).

The cross-linking activity of TG2 is strictly regulated. TG2 can take two conformations depending on whether Ca2+ or GTP/GDP is bound to the TG2 molecule: high [Ca2+] and low [GTP/GDP] (typically in extracellular space) favours the open conformation, where the site of cross-linking activity is exposed; intracellular TG2 is mainly in the closed conformation, with hidden site of cross-linking activity, but involved in signalling processes as a G-protein. Redox state of the TG2 surroundings affects the cross-linking activity, since a disulphide bond between adjacent cysteine residues leads to inactivation of TG2. Formation of ternary complexes with integrins and fibronectin may reduce the cross-linking activity, while other molecular stimuli can increase the activity.

The open conformation of TG2 is involved in celiac disease. In the fibrotic diseases TG2 is activated and overexpressed, increasing the production of scar tissue by cross-linking and stabilizing ECM proteins.

PET tracers

TG2 is a difficult target for in vivo imaging because of its different conformations and intra/extracellular localization. Labelled antibodies can target either open or closed conformation. Open conformation may be targeted by reversible and irreversible inhibitors developed for the cross-linking activity. GTP-binding domain of TG2 may be another target suitable for both antibodies and small molecule ligands.

Labelled antibodies, antibody fragments, and small organic molecules for TG2 in vivo imaging are being developed (van der Wildt et al., 2016 and 2017).


See also:



References:

Beninati S, Piacentini M, Bergamini CM. Transglutaminase 2, a double face enzyme. Amino Acids 2017; 49(3): 415-423.

Gundemir S, Colak G, Tucholski J, Johnson GV. Transglutaminase 2: a molecular Swiss army knife. Biochim Biophys Acta 2012; 1823(2): 406-419.

Keillor JW, Apperley KY, Akbar A. Inhibitors of tissue transglutaminase. Trends Pharmacol Sci. 2015; 36(1): 32-40.

van der Wildt B, Wilhelmus MM, Bijkerk J, Haveman LY, Kooijman EJ, Schuit RC, Bol JG, Jongenelen CA, Lammertsma AA, Drukarch B, Windhorst AD. Development of carbon-11 labeled acryl amides for selective PET imaging of active tissue transglutaminase. Nucl Med Biol. 2016; 43(4): 232-242.

van der Wildt B, Lammertsma AA, Drukarch B, Windhorst AD. Strategies towards in vivo imaging of active transglutaminase type 2 using positron emission tomography. Amino Acids 2017; 49(3): 585-595.

van der Wildt B, Wilhelmus MM, Kooijman EJ, Jongenelen CA, Schuit RC, B├╝chold C, Pasternack R, Lammertsma AA, Drukarch B, Windhorst AD. Development of fluorine-18 labeled peptidic PET tracers for imaging active tissue transglutaminase. Nucl Med Biol. 2017; 44: 90-104.



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Created at: 2017-03-05
Updated at: 2017-09-14
Written by: Vesa Oikonen