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Literature summary for 2.3.2.13 extracted from

  • Siegel, M.; Khosla, C.
    Transglutaminase 2 inhibitors and their therapeutic role in disease states (2007), Pharmacol. Ther., 115, 232-245.
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
medicine cystamine delays the onset of the neurological symptoms associated with Huntington’s disease when applied to the R6/2 Huntington’s mouse model, and dihydroisoxazoles, when used in tandem with BCNU, are able to decrease tumor size and extend survival in a mouse model of glioblastoma Mus musculus
medicine transglutaminase 2 is involved in the pathogenesis of a number of diseases, such as celiac sprue, neurodegenerative disorders, diabetes, liver cirrhosis and fibrosis, renal scarring, and certain types of cancer. It is the enzymatic function of TG2 that is thought to contribute to the pathology or etiology of most of the aforementioned diseases. Therefore, inhibition of the TG2 active site offers a potential strategy to therapeutically treat these disease Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
2-Iodoacetamide
-
Cavia porcellus
5-(biotinamido)pentylamine
-
Homo sapiens
cystamine
-
Homo sapiens
GDP
-
Homo sapiens
GTP causes significant shifts in electrophoretic mobility of the protein under native conditions Homo sapiens
Monodansylcadaverine
-
Homo sapiens
N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]-L-tryptophanamide
-
Homo sapiens
N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]tryptophanamide
-
Homo sapiens
N-[(6Z)-8-amino-2-[[(benzyloxy)carbonyl]amino]-8-oxooct-6-enoyl]glycine
-
Cavia porcellus
N-[[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]-L-tryptophanamide
-
Homo sapiens
Na-[(benzyloxy)carbonyl]-N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluorotryptophanamide
-
Homo sapiens
Nalpha-[(benzyloxy)carbonyl]-N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-L-tyrosinamide
-
Homo sapiens
putrescine
-
Homo sapiens
quinolin-3-ylmethyl [(1S)-2-([[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]methyl]amino)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate
-
Homo sapiens
quinolin-3-ylmethyl [(1S)-2-[[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]amino]-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate
-
Homo sapiens
[(2-[[(benzyloxy)carbonyl]amino]-4-[5-(formylamino)-1,2,4-thiadiazol-3-yl]butanoyl)amino]acetic acid
-
Cavia porcellus
[(4-[3-(aminocarbonyl)oxiran-2-yl]-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]acetic acid
-
Cavia porcellus
[([3-(aminocarbonyl)oxiran-2-yl][[(benzyloxy)carbonyl]amino]acetyl)amino]acetic acid
-
Cavia porcellus
[[(4E)-6-amino-2-[[(benzyloxy)carbonyl]amino]-6-oxohex-4-enoyl]amino]acetic acid
-
Cavia porcellus
[[(5E)-7-amino-2-[[(benzyloxy)carbonyl]amino]-7-oxohept-5-enoyl]amino]acetic acid
-
Cavia porcellus
[[(6Z)-8-amino-2-[[(benzyloxy)carbonyl]amino]-8-oxooct-6-enoyl]amino]acetic acid
-
Cavia porcellus

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol
-
Homo sapiens 5829
-
extracellular
-
Homo sapiens
-
-

Metals/Ions

Metals/Ions Comment Organism Structure
Ca2+ required Homo sapiens

Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
additional information
-
TG2 can assume multiple conformations Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
additional information Homo sapiens functions of TG2: wound healing, macrophage phagocytosis, TGF-beta activation, protein kinase activity, association with calreticulin, and association with G-protein coupled receptor GPR56. The majority of these functions are independent of the enzymatic transamidation activity of the protein. Transglutaminase 2 is involved in the pathogenesis of a number of diseases, such as celiac sprue, neurodegenerative disorders, diabetes, liver cirrhosis and fibrosis, renal scarring, and certain types of cancer. It is the enzymatic function of TG2 that is thought to contribute to the pathology or etiology of most of the aforementioned diseases ?
-
?

Organism

Organism UniProt Comment Textmining
Cavia porcellus
-
-
-
Homo sapiens
-
-
-
Mus musculus
-
-
-

Reaction

Reaction Comment Organism Reaction ID
protein glutamine + alkylamine = protein N5-alkylglutamine + NH3 the first step in both types of modifications is the acylation of the active site cysteine (Cys277) of TG2 by a protein-bound glutamine residue, resulting in the liberation of ammonia and the formation of a thioester intermediate between TG2 and the glutamine bearing protein substrate. In TG2 catalyzed transamidation, the thioester intermediate is attacked by a nucleophilic primary amine, either a small molecule amine such as putrescine or the epsilon-amino group of protein-bound lysine residues. This results in the formation of relatively stable isopeptide bonds Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
additional information TG2 shows an ubiquitous expression pattern of this protein throughout the body Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information functions of TG2: wound healing, macrophage phagocytosis, TGF-beta activation, protein kinase activity, association with calreticulin, and association with G-protein coupled receptor GPR56. The majority of these functions are independent of the enzymatic transamidation activity of the protein. Transglutaminase 2 is involved in the pathogenesis of a number of diseases, such as celiac sprue, neurodegenerative disorders, diabetes, liver cirrhosis and fibrosis, renal scarring, and certain types of cancer. It is the enzymatic function of TG2 that is thought to contribute to the pathology or etiology of most of the aforementioned diseases Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
TG2
-
Cavia porcellus
TG2
-
Mus musculus
TG2
-
Homo sapiens
transglutaminase 2
-
Cavia porcellus
transglutaminase 2
-
Mus musculus
transglutaminase 2
-
Homo sapiens

pH Range

pH Minimum pH Maximum Comment Organism
additional information
-
the transamidation reaction is kinetically favored over deamidation at pH-values above 7, but the deamidation reaction becomes kinetically competitive as the pH is lowered below 7 or as the concentration of amine substrates is lowered below their Km values Homo sapiens

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.000075
-
2-Iodoacetamide
-
Cavia porcellus
0.00028
-
[[(6Z)-8-amino-2-[[(benzyloxy)carbonyl]amino]-8-oxooct-6-enoyl]amino]acetic acid
-
Cavia porcellus
0.00048
-
[[(5E)-7-amino-2-[[(benzyloxy)carbonyl]amino]-7-oxohept-5-enoyl]amino]acetic acid
-
Cavia porcellus
0.00056
-
[([3-(aminocarbonyl)oxiran-2-yl][[(benzyloxy)carbonyl]amino]acetyl)amino]acetic acid
-
Cavia porcellus
0.0011
-
N-[(6Z)-8-amino-2-[[(benzyloxy)carbonyl]amino]-8-oxooct-6-enoyl]glycine
-
Cavia porcellus
0.00123
-
[(4-[3-(aminocarbonyl)oxiran-2-yl]-2-[[(benzyloxy)carbonyl]amino]butanoyl)amino]acetic acid
-
Cavia porcellus
0.0013
-
N-[[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]-L-tryptophanamide
-
Homo sapiens
0.00275
-
[[(4E)-6-amino-2-[[(benzyloxy)carbonyl]amino]-6-oxohex-4-enoyl]amino]acetic acid
-
Cavia porcellus
0.004
-
N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]-L-tryptophanamide
-
Homo sapiens
0.014
-
[(2-[[(benzyloxy)carbonyl]amino]-4-[5-(formylamino)-1,2,4-thiadiazol-3-yl]butanoyl)amino]acetic acid
-
Cavia porcellus
0.018
-
N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluoro-Na-[(quinolin-3-ylmethoxy)carbonyl]tryptophanamide
-
Homo sapiens
0.019
-
Na-[(benzyloxy)carbonyl]-N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-5-fluorotryptophanamide
-
Homo sapiens
0.03
-
quinolin-3-ylmethyl [(1S)-2-([[(5S)-3-bromo-4,5-dihydroisoxazol-5-yl]methyl]amino)-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate
-
Homo sapiens
0.041
-
quinolin-3-ylmethyl [(1S)-2-[[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]amino]-1-(4-hydroxybenzyl)-2-oxoethyl]carbamate
-
Homo sapiens
0.42
-
Nalpha-[(benzyloxy)carbonyl]-N-[(3-bromo-4,5-dihydroisoxazol-5-yl)methyl]-L-tyrosinamide
-
Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.009
-
-
Homo sapiens GTP