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  • Akbar, A.; McNeil, N.M.R.; Albert, M.R.; Ta, V.; Adhikary, G.; Bourgeois, K.; Eckert, R.L.; Keillor, J.W.
    Structure-activity relationships of potent, targeted covalent inhibitors that abolish both the transamidation and GTP binding activities of human tissue transglutaminase (2017), J. Med. Chem., 60, 7910-7927 .
    View publication on PubMedView publication on EuropePMC

Protein Variants

EC Number Protein Variants Comment Organism
2.3.2.13 additional information efficient site-specific antibody-drug conjugation by engineering a nature-derived recognition tag for microbial transglutaminase, overview Homo sapiens

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.3.2.13 (2S)-2-[[(benzyloxy)carbonyl]amino]-4-[(prop-2-enoyl)amino]butanoic acid
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-(4-acetylpiperazin-1-yl)-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-(4-benzoylpiperazin-1-yl)-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-(morpholin-4-yl)-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-1-[4-(phenylacetyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-1-[4-(phenylmethanesulfonyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-1-[4-(propane-2-sulfonyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-6-[(prop-2-enoyl)amino]-1-[4-(pyridine-2-carbonyl)piperazin-1-yl]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-6-[(prop-2-enoyl)amino]-1-[4-(pyridine-3-carbonyl)piperazin-1-yl]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-6-[(prop-2-enoyl)amino]-1-[4-(pyridine-4-carbonyl)piperazin-1-yl]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-oxo-6-[(prop-2-enoyl)amino]-1-[4-(thiophene-2-sulfonyl)piperazin-1-yl]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[(2-aminoethyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[(3-aminopropyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[(4-aminobutyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(2-chlorophenyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(7-hydroxy-2-oxo-2H-1-benzopyran-3-carbonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate i.e. VA5 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(benzenesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(cyclohexanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(ethanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(methanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(naphthalene-1-carbonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(naphthalene-1-sulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(naphthalene-2-carbonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-(naphthalene-2-sulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-5-[(prop-2-enoyl)amino]pentan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate
-
 Homo sapiens
2.3.2.13 benzyl [(9S)-19-[[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-3,10-dioxo-14,17-dioxa-4,11-diazanonadec-1-en-9-yl]carbamate
-
 Homo sapiens
2.3.2.13 methyl N2-[(benzyloxy)carbonyl]-N6-(prop-2-enoyl)-L-lysylglycinate
-
 Homo sapiens
2.3.2.13 additional information efficient site-specific antibody-drug conjugation by engineering a nature-derived recognition tag for microbial transglutaminase, overview. Synthesis and evaluation of series of targeted covalent inhibitors (TCIs) whose structure is based on a Cbz-Lys scaffold, the irreversible inhibitors block both the transamidation and GTP-binding activities of hTG2, structure-activity relationship (SAR) study and docking study using crystal structure PDB ID 2Q3Z. Isozyme selectivity. No inhibition by benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-3-[(prop-2-enoyl)amino]propan-2-yl]carbamate and benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-4-[(prop-2-enoyl)amino]butan-2-yl]carbamate Homo sapiens
2.3.2.13 N,N-dimethyl-5-(piperazine-1-sulfonyl)naphthalen-1-amine
-
 Homo sapiens
2.3.2.13 N-(2-aminoethyl)-5-(dimethylamino)naphthalene-1-sulfonamide
-
 Homo sapiens
2.3.2.13 N-(3-aminopropyl)-5-(dimethylamino)naphthalene-1-sulfonamide
-
 Homo sapiens
2.3.2.13 N-(4-aminobutyl)-5-(dimethylamino)naphthalene-1-sulfonamide
-
 Homo sapiens
2.3.2.13 N-[(benzyloxy)carbonyl]-3-[(prop-2-enoyl)amino]-L-alanine
-
 Homo sapiens
2.3.2.13 N2-[(benzyloxy)carbonyl]-N5-prop-2-enoyl-L-ornithine
-
 Homo sapiens
2.3.2.13 N2-[(benzyloxy)carbonyl]-N6-(prop-2-enoyl)-L-lysylglycine
-
 Homo sapiens
2.3.2.13 N2-[(benzyloxy)carbonyl]-N6-prop-2-enoyl-L-lysinamide
-
 Homo sapiens
2.3.2.13 N2-[(benzyloxy)carbonyl]-N6-prop-2-enoyl-L-lysine
-
 Homo sapiens
2.3.2.13 VA4 the inhibitor also inhibits epidermal cancer stem cell invasion with an EC50 of 0.0039 mM Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.3.2.13 extracellular extracellular matrix Homo sapiens
-
-
2.3.2.13 plasma membrane
-
 Homo sapiens 5886
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.3.2.13 Ca2+ required, hTG2 is allosterically modulated by calcium ions Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.3.2.13 protein glutamine + alkylamine Homo sapiens
-
 protein N5-alkylglutamine + NH3
-
 ?

Organism

EC Number Organism UniProt Comment Textmining
2.3.2.13 Homo sapiens
-
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.3.2.13 additional information hTG2 is a ubiquitously expressed enzyme Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.3.2.13 protein glutamine + alkylamine
-
 Homo sapiens protein N5-alkylglutamine + NH3
-
 ?

Synonyms

EC Number Synonyms Comment Organism
2.3.2.13 hTG2
-
 Homo sapiens
2.3.2.13 microbial transglutaminase
-
 Homo sapiens
2.3.2.13 tissue transglutaminase
-
 Homo sapiens

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.3.2.13 25
-
 assay at Homo sapiens

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.3.2.13 6.5 7 assay at Homo sapiens

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
2.3.2.13 additional information
-
 additional information inhibition kinetic analysis Homo sapiens
2.3.2.13 0.0064
-
 benzyl [(2S)-1-[4-(methanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0067
-
 benzyl [(2S)-1-[4-(naphthalene-2-sulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0088
-
 benzyl [(2S)-1-[4-(benzenesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0089
-
 benzyl [(2S)-1-[4-(naphthalene-1-carbonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0091
-
 benzyl [(2S)-1-oxo-1-[4-(propane-2-sulfonyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0104
-
 benzyl [(2S)-1-[4-(naphthalene-1-sulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.011
-
 benzyl [(2S)-1-[4-(cyclohexanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0129
-
 benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0134
-
 benzyl [(2S)-1-[4-(naphthalene-2-carbonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0147
-
 benzyl [(2S)-1-oxo-1-[4-(phenylmethanesulfonyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.02
-
 benzyl [(2S)-1-oxo-1-[4-(phenylacetyl)piperazin-1-yl]-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0235
-
 benzyl [(2S)-1-[(2-aminoethyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0271
-
 benzyl [(2S)-1-[(4-aminobutyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0305
-
 benzyl [(2S)-1-[(3-aminopropyl)[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0339
-
 benzyl [(9S)-19-[[5-(dimethylamino)naphthalene-1-sulfonyl]amino]-3,10-dioxo-14,17-dioxa-4,11-diazanonadec-1-en-9-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0351
-
 N2-[(benzyloxy)carbonyl]-N6-prop-2-enoyl-L-lysinamide pH 6.5, 25°C Homo sapiens
2.3.2.13 0.036
-
 benzyl [(2S)-1-[4-(ethanesulfonyl)piperazin-1-yl]-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0366
-
 benzyl [(2S)-1-(4-benzoylpiperazin-1-yl)-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.04
-
 methyl N2-[(benzyloxy)carbonyl]-N6-(prop-2-enoyl)-L-lysylglycinate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0401
-
 benzyl [(2S)-1-oxo-6-[(prop-2-enoyl)amino]-1-[4-(thiophene-2-sulfonyl)piperazin-1-yl]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0477
-
 benzyl [(2S)-1-[4-[5-(dimethylamino)naphthalene-1-sulfonyl]piperazin-1-yl]-1-oxo-5-[(prop-2-enoyl)amino]pentan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0481
-
 N2-[(benzyloxy)carbonyl]-N6-(prop-2-enoyl)-L-lysylglycine pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0521
-
 benzyl [(2S)-1-(4-acetylpiperazin-1-yl)-1-oxo-6-[(prop-2-enoyl)amino]hexan-2-yl]carbamate pH 6.5, 25°C Homo sapiens
2.3.2.13 0.0603
-
 N2-[(benzyloxy)carbonyl]-N6-prop-2-enoyl-L-lysine pH 6.5, 25°C Homo sapiens

General Information

EC Number General Information Comment Organism
2.3.2.13 additional information in the open active conformation, the catalytic core, which contains the catalytic triad Cys277, His335, and Asp358, is accessible and capable of catalyzing the formation of isopeptide bonds (cross-links) between peptide bound Gln and Lys residues. The cross-linking activity is also referred to as transamidation and occurs via a ping-pong mechanism. First, the nucleophilic active site thiolate (Cys277) attacks an acyl donor substrate (i.e. a peptide-bound Gln residue) resulting in the release of one equivalent of ammonia and the formation of the intermediate thioester. Subsequently, the thiolate is regenerated by nucleophilic attack of an acyl acceptor substrate (i.e. a peptide-bound Lys residue) to afford the isopeptide product, or the thioester is cleaved by water to afford the deamidated (or hydrolysis) product. Upon GTP binding, hTG2 primarily adopts a closed or compact conformation where the catalytic Cys277 becomes inaccessible Homo sapiens
2.3.2.13 physiological function human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. hTG2 function is tightly regulated by the presence of specific allosteric and redox regulators. Enzyme hTG2 is allosterically modulated by calcium ions and redox proteins to primarily exist in an open or extended conformation that is catalytically active when specific disulfide bonds are reduced. Intracellularly, hTG2 is regulated by guanidine-containing nucleotides, such as GTP that bind hTG2 at a site remote from the catalytic active site. The enzyme is implicated in several disease processes Homo sapiens