Literature summary for 2.3.2.2 extracted from

Kamiyama, A.; Nakajima, M.; Han, L.; Wada, K.; Mizutani, M.; Tabuchi, Y.; Kojima-Yuasa, A.; Matsui-Yuasa, I.; Suzuki, H.; Fukuyama, K.; Watanabe, B.; Hiratake, J.
Phosphonate-based irreversible inhibitors of human gamma-glutamyl transpeptidase (GGT). GGsTop is a non-toxic and highly selective inhibitor with critical electrostatic interaction with an active-site residue Lys562 for enhanced inhibitory activity (2016), Bioorg. Med. Chem., 24, 5340-5352 .

Cloned(Commentary)

Cloned (Comment)	Organism
gene ggt, recombinant expression of wild-type and K562S mutant enzymes in Spodoptera frugiperda Sf9 cells via baculovirus transfection method	Homo sapiens

Protein Variants

Protein Variants	Comment	Organism
K562S	site-directed mutagenesis, the mutant shows reduced activity compared to wild-type: the mutant's affinity towards Gly-Gly dramatically decreases to 2.0% of wild-type level, whereas it retains 45% of wild-type hydrolytic activity	Homo sapiens
K568S	site-directed mutagenesis, the mutant shows highly reduced activity compared to wild-type	Homo sapiens
additional information	the N-terminal anchor domain of enzyme GGT is truncated, human GGT protein without the anchor domain is expressed as a soluble enzyme, and it exhibits virtually identical enzymatic character to that of wild-type human GGT with the anchor domain. The wild-type human GGT is expressed as a mature protein by autocatalytic processing during the period of infection. The autocatalytic process of K562S mutant is somewhat slow and is not enough under the same conditions, but the successful processing is attained by giving additional processing period for the purification step	Homo sapiens

Inhibitors

Inhibitors	Comment	Organism
(2RS,RPSP)-2-amino-4-(diphenoxyphosphoryl)butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[(3-carboxyphenoxy)(methoxy)phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[(4-carboxyphenoxy)(methoxy)phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[bis[(3-carboxymethy)lphenoxy]phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[[3-(2-carboxyethyl)phenoxy](methoxy)phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[[3-(carbamoylmethyl)phenoxy](methoxy)phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[[3-(ethoxycarbonylmethyl)phenoxy](methoxy)phosphoryl]butanoic acid	-	Homo sapiens
(2RS,RPSP)-2-amino-4-[[3-nitrophenoxy](methoxy)phosphoryl]butanoic acid	-	Homo sapiens
2-amino-4-([3-(carboxymethyl)phenoxy](methoyl)phosphoryl)butanoic acid	i.e. GGsTop, weak inhibition, structure-activity relationship, Escherichia coli enzyme GGT in complex with the inhibitor, Lys562 is the probable residue for the recognition of negative charge at C-terminal of GGsTop	Escherichia coli
2-amino-4-([3-(carboxymethyl)phenoxy](methoyl)phosphoryl)butanoic acid	i.e. GGsTop. GGsTop shows no cytotoxicity toward human fibroblasts and hepatic stellate cells up to 1 mM. GGsTop serves as a non-toxic, selective and highly potent irreversible GGT inhibitor that can be used for various in vivo as well as in vitro biochemical studies. Lys562 of human GGT is the key residue for the recognition of the negatively charged GGsTop. The active site Lys562 of human GGT enhances the inhibitory activity of GGsTop by 128fold. GGsTop does not induce cytotoxicity for mammalian cells at up to 1 mM	Homo sapiens
acivicin	-	Escherichia coli
acivicin	-	Homo sapiens
additional information	evaluation of a phosphonate-based irreversible inhibitor, 2-amino-4-([3-(carboxymethyl)phenoxy](methoyl)phosphoryl)butanoic acid (GGsTop) and its analogues as a mechanism-based inhibitor of human GGT. GGsTop is a stable compound, but inactivates the human enzyme significantly faster than the other phosphonates, and importantly does not inhibit a glutamine amidotransferase. Structure-activity relationships, overview	Homo sapiens

Localization

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

Natural Substrates/ Products (Substrates)

Natural Substrates	Organism	Comment (Nat. Sub.)	Natural Products	Comment (Nat. Pro.)	Rev.
a (5-L-glutamyl)-peptide + an amino acid	Homo sapiens	-	a peptide + a 5-L-glutamyl amino acid	-	?
a (5-L-glutamyl)-peptide + an amino acid	Escherichia coli	-	a peptide + a 5-L-glutamyl amino acid	-	?
a (5-L-glutamyl)-peptide + an amino acid	Escherichia coli K12	-	a peptide + a 5-L-glutamyl amino acid	-	?
additional information	Homo sapiens	GGT is an extracellular enzyme and catalyzes the cleavage of the gamma-glutamyl amide bond of glutathione by a modified ping-pong mechanism via a gamma-glutamyl-enzyme ester intermediate to transfer the c-glutamyl group to water (hydrolysis) or amino acids and peptides (transpeptidation)	?	-	-

Organism

Organism	UniProt	Comment	Textmining
Escherichia coli	P18956	-	-
Homo sapiens	P19440	-	-

Substrates and Products (Substrate)

Substrates	Comment Substrates	Organism	Products	Comment (Products)	Rev.
a (5-L-glutamyl)-peptide + an amino acid	-	Homo sapiens	a peptide + a 5-L-glutamyl amino acid	-	?
a (5-L-glutamyl)-peptide + an amino acid	-	Escherichia coli	a peptide + a 5-L-glutamyl amino acid	-	?
a (5-L-glutamyl)-peptide + an amino acid	-	Escherichia coli K12	a peptide + a 5-L-glutamyl amino acid	-	?
L-gamma-glutamyl-4-nitroanilide + glycine methylester	very low activity	Homo sapiens	4-nitroaniline + 5-L-glutamyl-glycyl methylester	-	?
L-gamma-glutamyl-4-nitroanilide + glycylglycine	-	Homo sapiens	4-nitroaniline + 5-L-glutamyl-glycylglycine	-	?
L-gamma-glutamyl-4-nitroanilide + glycylglycine methylester	low activity	Homo sapiens	4-nitroaniline + 5-L-glutamyl-glycylglycine methylester	-	?
additional information	GGT is an extracellular enzyme and catalyzes the cleavage of the gamma-glutamyl amide bond of glutathione by a modified ping-pong mechanism via a gamma-glutamyl-enzyme ester intermediate to transfer the c-glutamyl group to water (hydrolysis) or amino acids and peptides (transpeptidation)	Homo sapiens	?	-	-
additional information	GGT not only catalyzes the transfer of gamma-glutamyl group of gamma-Glu-PNA to acceptors, but also hydrolyzes the gamma-glutamyl bond of gamma-Glu-PNA to give glutamate and 4-nitroaniline (EC 3.4.19.13)	Homo sapiens	?	-	-

Subunits

Subunits	Comment	Organism
heterodimer	-	Homo sapiens
heterodimer	-	Escherichia coli

Synonyms

Synonyms	Comment	Organism
gamma-glutamyl transpeptidase	-	Homo sapiens
gamma-glutamyl transpeptidase	-	Escherichia coli
GGT	-	Homo sapiens
GGT	-	Escherichia coli
More	cf. EC 3.4.19.13	Homo sapiens

Ki Value [mM]

Ki Value [mM]	Ki Value maximum [mM]	Inhibitor	Comment	Organism	Structure
additional information	-	additional information	inhibition kinetics, overview	Homo sapiens
additional information	-	additional information	inhibition kinetics, overview	Escherichia coli

General Information

General Information	Comment	Organism
malfunction	human GGT protein without the N-terminal anchor domain is expressed as a soluble enzyme and it exhibits virtually identical enzymatic character to that of wild-type human GGT with the anchor domain	Homo sapiens
physiological function	gamma-glutamyl transpeptidase (GGT) catalyzes the hydrolysis (EC 3.4.19.13) and transpeptidation of glutathione and its S-conjugates is involved in a number of physiological and pathological processes through glutathione metabolism	Homo sapiens