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Literature summary for 2.3.2.13 extracted from
- Substrates, inhibitors, and probes of mammalian transglutaminase 2 (2020), Anal. Biochem., 591, 113560 .
Crystallization (Commentary)
| Crystallization (Comment) | Organism |
|---|---|
| human TG2 has been crystallized in its GDP- and GTP-bound form (PDB IDs 1KV3, 4PYG), in complex with ATP (PDB ID 3LY6), and with alternative inhibitors bound to its transamidase site within the alpha/beta-catalytic domain (PDB IDs 2Q3Z, 3S3J, 3S3P, 3S3S), structure modeling, analysis, overview | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 5-biotinamido pentylamine | 5BP, 5BP is widely used in chromogenic TG2 assays, based on the ability of streptavidin conjugates to recognize its biotin substituent with high specificity | Homo sapiens |  |
| 6-diazo-5-oxo-L-norleucine | DON | Homo sapiens | |
| monodansyl cadaverine | MDC | Homo sapiens | |
| additional information | peptide harboring Gln mimics, e.g. 6-diazo-5-oxo-L-norleucine, have the potential to show considerably higher specificity for TG2 than the amine inhibitors. Non-hydrolyzable GTP analogs (e.g. 5'-guanylyl imidodiphosphate) are also inhibitors of TG2 activity. Because of the tight coupling between the GTP binding site and the transamidase/deamidase active site of TG2, these ligands act as competitive inhibitors of both the GTPase and transglutaminase activities of this enzyme | Homo sapiens |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | transglutaminase activity requires multiple Ca2+ ions | Homo sapiens | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| beta-crystallin glutamine + alkylamine | Homo sapiens | beta-crystallin, a major structural protein of the eye lens, is an archetypal TG2 substrate. Its target Gln residue is localized to a peptide sequence denoted A25 (TVQQEL), and is crosslinked to a Lys residue near the C-terminus of the same protein | beta-crystallin N5-alkylglutamine + NH3 | - |
? | |
| fibronectinglutamine + alkylamine | Homo sapiens | the 220 kDa fibronectin monomer harbors multiple Gln residues susceptible to TG2 modification, including sites within its N-terminal collagen/fibrinbinding domain, its central (RGD-containing) integrin-binding domain, and its C-terminal glycosaminoglycan-binding domain. In addition, its N-terminal domain also harbors a high-affinity non-covalent docking site for TG2 | fibronectin N5-alkylglutamine + NH3 | - |
? | |
| additional information | Homo sapiens | certain gluten peptides are excellent TG2 substrates, prompting analysis of the enzyme's substrate specificity. The most favorable substrates appear to harbor a reactive Gln within a Q-X-P motif, whereas sequences containing Q-P, Q-G, Q-X-X-P, or Q-X-X-G motifs are not recognized (X denotes any amino acid). A random 7-mer peptide library yields GQQQTPY, GLQQASV and WQTPMNS as preferred substrates of TG2 | ? | - |
- |
|
| protein glutamine + alkylamine | Homo sapiens | - |
protein N5-alkylglutamine + NH3 | - |
? | |
| transforming growth factor-beta glutamine + alkylamine | Homo sapiens | - |
transforming growth factor-beta N5-alkylglutamine + NH3 | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P21980 | - |
- |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| beta-crystallin glutamine + alkylamine | - |
Homo sapiens | beta-crystallin N5-alkylglutamine + NH3 | - |
? | |
| beta-crystallin glutamine + alkylamine | beta-crystallin, a major structural protein of the eye lens, is an archetypal TG2 substrate. Its target Gln residue is localized to a peptide sequence denoted A25 (TVQQEL), and is crosslinked to a Lys residue near the C-terminus of the same protein | Homo sapiens | beta-crystallin N5-alkylglutamine + NH3 | - |
? | |
| fibronectinglutamine + alkylamine | - |
Homo sapiens | fibronectin N5-alkylglutamine + NH3 | - |
? | |
| fibronectinglutamine + alkylamine | the 220 kDa fibronectin monomer harbors multiple Gln residues susceptible to TG2 modification, including sites within its N-terminal collagen/fibrinbinding domain, its central (RGD-containing) integrin-binding domain, and its C-terminal glycosaminoglycan-binding domain. In addition, its N-terminal domain also harbors a high-affinity non-covalent docking site for TG2 | Homo sapiens | fibronectin N5-alkylglutamine + NH3 | - |
? | |
| additional information | certain gluten peptides are excellent TG2 substrates, prompting analysis of the enzyme's substrate specificity. The most favorable substrates appear to harbor a reactive Gln within a Q-X-P motif, whereas sequences containing Q-P, Q-G, Q-X-X-P, or Q-X-X-G motifs are not recognized (X denotes any amino acid). A random 7-mer peptide library yields GQQQTPY, GLQQASV and WQTPMNS as preferred substrates of TG2 | Homo sapiens | ? | - |
- |
|
| additional information | enzyme transglutaminase 2 (TG2) can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. It is also known to harbor other enzymatic properties, including protein disulfide isomerase, GTP-dependent signal transduction, and ATP dependent protein kinase activity | Homo sapiens | ? | - |
- |
|
| protein glutamine + alkylamine | - |
Homo sapiens | protein N5-alkylglutamine + NH3 | - |
? | |
| transforming growth factor-beta glutamine + alkylamine | - |
Homo sapiens | transforming growth factor-beta N5-alkylglutamine + NH3 | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| TG2 | - |
Homo sapiens |
| transglutaminase 2 | - |
Homo sapiens |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ERp57 | TG2 cofactors TRX and ERp57 reversibly regulate TG2 in a redox-dependent manner, and act as on and off switches for the active enzyme | Homo sapiens | |
| thioredoxin | TRX, TG2 cofactors TRX and ERp57 reversibly regulate TG2 in a redox-dependent manner, and act as on and off switches for the active enzyme | Homo sapiens | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | as a member of the transglutaminase family, transglutaminase 2 (TG2) can catalyze deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. Redox regulation unique to TG2 and evolved relatively recently, TG2 homologues in other vertebrates appear to lack this structure feature | Homo sapiens |
| metabolism | regulation of human TG2, overview. Redox regulation unique to this isozyme | Homo sapiens |
| additional information | transglutaminase 2 (TG2) is the only mammalian transglutaminase to harbor the conserved Cys-triad | Homo sapiens |
| physiological function | enzyme transglutaminase 2 (TG2) catalyzes deamidation or alternatively transamidation of selected Gln residues in proteins and peptides. As TG2 is natively inactive, TRX is able to reduce the vicinal disulfide bond between C370-C371 to activate TG2, and ERp57 can oxidize the disulfide between C230 and C370 to catalytically inactivate the enzyme. Redox regulation of human TG2, overview. The 220 kDa fibronectin monomer harbors multiple Gln residues susceptible to TG2 modification, including sites within its N-terminal collagen/fibrinbinding domain, its central (RGD-containing) integrin-binding domain, and its C-terminal glycosaminoglycan-binding domain. In addition, its N-terminal domain also harbors a high-affinity non-covalent docking site for TG2. Remarkably, the biogenic amine serotonin can serve as an effective nucleophile in TG2-catalyzed modification of fibronectin; this post-translational modification of fibronectin appears to be a biomarker of pulmonary hypertension in humans as well as cellular and animal models of the disease. Like fibronectin, a number of other proteins comprising the extracellular matrix have been shown to harbor TG2-reactive sites. Amongst these, TG2-catalyzed crosslinking of the amino-propeptide of type III collagen onto the mature collagen fibril and the oligomerization of osteonectin in the matrix of differentiating cartilage represent especially intriguing examples, notwithstanding very limited insight into their biological relevance. TG2 catalyzes an early step in the activation of transforming growth factor-beta (TGF-beta) by crosslinking latent TGF-beta binding protein (LTBP) to the extracellular matrix. Two classes of non-physiological substrates of TG2 warrant attention. The first includes peptides derived from dietary gluten | Homo sapiens |
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