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Information on EC 3.4.19.13 - glutathione gamma-glutamate hydrolase and Organism(s) Escherichia coli and UniProt Accession P18956

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EC Tree
     3 Hydrolases
         3.4 Acting on peptide bonds (peptidases)
             3.4.19 Omega peptidases
                3.4.19.13 glutathione gamma-glutamate hydrolase
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Escherichia coli
UNIPROT: P18956 not found.
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The taxonomic range for the selected organisms is: Escherichia coli
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Synonyms
hp1118, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
gamma-glutamyl transpeptidase
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PATHWAY SOURCE
PATHWAYS
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-, -, -, -, -, -, -
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
glutathione + H2O
L-cysteinylglycine + L-glutamate
show the reaction diagram
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the reaction consists of two steps. First the active O atom of Thr391 attacks the carbonyl carbon atom of the gamma-glutamyl compound to form the gamma-glutamyl-enzyme intermediate, and then the gamma-glutamyl moiety is transferred to another substrate, i.e. reaction of EC 2.3.2.2, or the gamma-glutamyl-enzyme bond is hydrolyzed to reform the resting enzyme. The second step of the reaction, the hydrolysis of the intermediate, is much slower than the first reaction step
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?
7-(gamma-L-glutamylamino)-4-methylcoumarin + H2O
7-amino-4-methylcoumarin + L-glutamate
show the reaction diagram
-
-
-
-
?
additional information
?
-
residue Thr391, the N-terminal residue of the small subunit, is the nucleophile for the enzymatic reaction
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-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2-amino-4-[[3-(carboxymethyl)phenoxy](methoxy)phosphoryl] butanoic acid
the mechanism-based inhibitor
(2RS)-2-amino-4-((R)-1-[N-(carboxymethyl)carbamoyl]-2-chloroethyl(phenyl)-phosphono)butanoic acid
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potent and irreversible inhibitor of enzyme, second-order rate constant value 188 per M and s, and good mimic of the putative transition state
(2RS)-2-amino-4-((S)-1-[N-(carboxymethyl)carbamoyl]-2-phenylethyl(phenyl)-phosphono)butanoic acid
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potent and irreversible inhibitor of enzyme, second-order rate constant value 389 per M and s, and good mimic of the putative transition state
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
phylogenetic analysis of gamma-glutamyltranspeptidase proteins from different organisms divides the gamma-glutamyltranspeptidases into various clades and offers several interesting insights into the evolution and relatedness of these gamma-glutamyltranspeptidases. The present study focuses on the residues that are highly specific to each gamma-glutamyltranspeptidase subfamily and underlines their importance in imparting unique functional properties to the gamma-glutamyltranspeptidase proteins of each clade. The present study highlights the clade specific variation in the GXXGG motif, where SP (XX) of bacterial gamma-glutamyltranspeptidases is substituted by VM, CA, AS in extremophilic bacteria, archaea, and eukaryotes respectively, which could explain the differences in rates of enzyme reaction in gamma-glutamyltranspeptidases of these clades as this motif is known to be involved in gamma-glutamyltranspeptidase-substrate complex intermediate formation and the rate of final product release. Many sites predicted to be contributing to type 2 functional divergence are quite often found lining the substrate binding cavity and are close to the highly conserved known functional residues. This implies that they may be affecting the biochemical environment of the binding cavity and influencing the catalytic residues, thereby contributing to the functional differences among gamma-glutamyltranspeptidase-like proteins of various clades
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
20000
x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
40000
x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
60000
x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
?
x * 60000, proenzyme, x * 40000, large subunit, plus x * 20000, small subunit, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
proteolytic modification
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
mutant T391A, unable to undergo autocatalytic processing, at 2.55 A resolution. Structural comparison of the precursor and mature protein demonstrates that the structures of the core regions in the two proteins are unchanged, with marked differences near the active site. In the precursor, the segment corresponding to the C-terminal region of the L-subunit occupies the site where the loop, residues 438-449, forms the lid of the gamma-glutamyl group-binding pocket in the mature enzyme. Upon cleavage of the N-terminal peptide bond of Thr391, the newly produced C-terminus, residues 375–390, flips out, allowing the 438-449 segment to form the gamma-glutamyl group-binding pocket. A water molecule is located near the carbonyl carbon atom of Gln-390. The spatial arrangement around the water and Thr391 relative to the scissile peptide bond appears suitable for the initiation of autocatalytic processing
to 1.95 A resolution. The enzyme has a stacked alphabetabetaalpha fold comprising the large and small subunits, similar to the folds seen in members of the N-terminal nucleophile hydrolase superfamily. The active site residue Thr391, the N-terminal residue of the small subunit, is located in the groove, from which the pocket for gamma-glutamyl moiety binding follows. The gamma-glutamyl-enzyme intermediate and the structure of the complex with L-glutamate reveal how the gamma-glutamyl moiety and L-glutamate are recognized by the enzyme. A water molecule is seen on the carbonyl carbon of the gamma-glutamyl-Thr391 O bond in the intermediate that is to be hydrolyzed. The residues essential for enzymic activity, i.e. Arg114, Asp433, Ser462, and Ser463, are all involved in the binding of the gamma-glutamyl moiety
X-ray crystallography of the enzyme in complex with inhibitor 2-amino-4-[[3-(carboxymethyl)phenoxy](methoyl)phosphoryl] butanoic acid
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
T391A
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pharmacology
the enzyme is involved in a number of physiological and pathological processes through glutathione metabolism and is an attractive pharmaceutical target
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Okada, T.; Suzuki, H.; Wada, K.; Kumagai, H.; Fukuyama, K.
Crystal structure of the gamma-glutamyltranspeptidase precursor protein from Escherichia coli. Structural changes upon autocatalytic processing and implications for the maturation mechanism
J. Biol. Chem.
282
2433-2439
2007
Escherichia coli (P18956)
Manually annotated by BRENDA team
Okada, T.; Suzuki, H.; Wada, K.; Kumagai, H.; Fukuyama, K.
Crystal structures of gamma-glutamyltranspeptidase from Escherichia coli, a key enzyme in glutathione metabolism, and its reaction intermediate
Proc. Natl. Acad. Sci. USA
103
6471-6476
2006
Escherichia coli (P18956)
Manually annotated by BRENDA team
Suzuki, H.; Kumagai, H.
Autocatalytic processing of gamma-glutamyltranspeptidase
J. Biol. Chem.
277
43536-43543
2002
Escherichia coli (P18956)
Manually annotated by BRENDA team
Nakajima, M.; Watanabe, B.; Han, L.; Shimizu, B.; Wada, K.; Fukuyama, K.; Suzuki, H.; Hiratake, J.
Glutathione-analogous peptidyl phosphorus esters as mechanism-based inhibitors of gamma-glutamyl transpeptidase for probing cysteinyl-glycine binding site
Bioorg. Med. Chem.
22
1176-1194
2014
Escherichia coli, Homo sapiens
Manually annotated by BRENDA team
Verma, V.V.; Gupta, R.; Goel, M.
Phylogenetic and evolutionary analysis of functional divergence among Gamma glutamyl transpeptidase (GGT) subfamilies
Biol. Direct
10
49
2015
Bacillus anthracis (Q51693), Bacillus subtilis, Bacillus subtilis BEST7613, Escherichia coli (P18956), Escherichia coli K12 (P18956), Halalkalibacterium halodurans, Helicobacter pylori (Q9F5N9), Homo sapiens (P19440), Saccharomyces cerevisiae (Q05902), Saccharomyces cerevisiae ATCC 204508 (Q05902), Thermoplasma acidophilum (Q9HJH4), Thermoplasma acidophilum ATCC 25905 (Q9HJH4)
Manually annotated by BRENDA team
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
Bioorg. Med. Chem.
24
5340-5352
2016
Escherichia coli (P18956), Escherichia coli K12 (P18956), Homo sapiens (P19440)
Manually annotated by BRENDA team