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Information on EC 3.4.17.21 - Glutamate carboxypeptidase II and Organism(s) Mus musculus and UniProt Accession Q9CZR2
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3.4.17.21 Glutamate carboxypeptidase IISpecify your search results
Word Map
- 3.4.17.21
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tomography
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positron
- metastases
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psma-targeted
- node
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lncap
-
tracer
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prostatectomy
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castration-resistant
-
modal
-
radioligands
- androgen
-
psma-positive
-
radiotherapy
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radionuclide
-
68ga-psma
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biodistribution
-
radiotracers
-
neovasculature
-
radiopharmaceutical
-
mcrpc
-
theranostic
-
pelvic
-
gleason
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psma-expressing
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suvmax
-
restaging
-
oligometastatic
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68ga-labeled
-
multiparametric
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urea-based
-
spect
-
dosimetry
-
scintigraphy
- abiraterone
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castrate-resistant
- n-acetylaspartate
-
extraprostatic
-
mpmri
-
pet-ct
-
enzalutamide
-
18f-labeled
-
positron-emission
-
tomography-computed
-
radium-223
- pharmacology
-
radioimmunotherapy
- medicine
-
tumor-to-background
- analysis
-
radiometals
-
postprostatectomy
-
per-patient
- diagnostics
- drug development
The taxonomic range for the selected organisms is: Mus musculus
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
The expected taxonomic range for this enzyme is: Bacteria, Eukaryota, Archaea
Reaction Schemes
release of an unsubstituted, C-terminal glutamyl residue, typically from Ac-Asp-Glu or folylpoly-gamma-glutamates
Synonyms
prostate-specific membrane antigen, gcpii, prostate specific membrane antigen, glutamate carboxypeptidase ii, naaladase, gcp ii, folh1, folate hydrolase, naag peptidase, n-acetylated alpha-linked acidic dipeptidase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
100 kDa ileum brush border membrane protein
-
-
-
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Acetylaspartylglutamate dipeptidase
-
-
-
-
Dipeptidase, acetylaspartylglutamate
-
-
-
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FGCP
-
-
-
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Folylpoly-gamma-glutamate carboxypeptidase
-
-
-
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GCPII
glutamate carboxypeptidase II
I100
-
-
-
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Ileal dipeptidylpeptidase
-
-
-
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Membrane glutamate carboxypeptidase
-
-
-
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mGCP
-
-
-
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N-Acetylated alpha-linked acidic dipeptidase
N-Acetylated-alpha-linked acidic dipeptidase
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-
-
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N-Acetylated-alpha-linked-acidic dipeptidase
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-
-
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N-Acetylated-alpha-linked-amino dipeptidase
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-
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NAALA dipeptidase
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-
-
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NAALADase
Prostate-specific membrane antigen
Prostate-specific membrane antigen homolog
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-
-
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Prostrate-specific membrane antigen
-
-
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PSM
-
-
-
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PSM antigen
-
-
-
-
PSMA
Pteroylpoly-gamma-glutamate carboxypeptidase
-
-
-
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Rat NAAG peptidase
-
-
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N-Acetylated alpha-linked acidic dipeptidase
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-
-
-
NAALADase
-
-
-
-
Prostate-specific membrane antigen
-
-
-
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PSMA
-
-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of peptide bond
hydrolysis of peptide bond
-
-
-
-
PATHWAY SOURCE
PATHWAYS
CAS REGISTRY NUMBER
COMMENTARY
111070-04-3
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
N-acetyl-alpha L-aspartyl-L-glutamate + H2O
N-acetyl-L-aspartate + L-glutamate
-
-
-
-
?
N-acetyl-L-aspartyl-L-glutamate + H2O
N-acetyl-L-aspartate + L-glutamate
-
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
the enzyme inactivates the neurotransmitter in the synaptic cleft
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
i.e. NAAG
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
-
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
i.e. NAAG, a neurodipeptide, the enzyme acts as membrane-bound receptor being recycled through clathrin coated pits, expression regulation within cells in prostate cancer and metastasis, overview
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
the enzyme is responsible for glutamate supply, enzyme inhibition decreases the glutamate and increases the N-acetyl-alpha-L-aspartyl-L-glutamate concentration in the brain, which can be a method to treat opioid tolerance and diminish effects of morphine withdrawal, overview
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-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
i.e. NAAG
-
-
?
additional information
?
-
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the enzyme interacts with filamin leading to internalization of PMSA into cells in the perinuclear region, overview
-
-
?
additional information
?
-
-
bifunctional enzyme performing folate hydrolase and N-acetylated alpha-linked acidic dipeptidase, NAALADase, activities
-
-
?
additional information
?
-
mouse glutamate carboxypeptidase II possesses lower catalytic efficiency but similar substrate specificity compared with the human protein
-
-
?
additional information
?
-
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mouse glutamate carboxypeptidase II possesses lower catalytic efficiency but similar substrate specificity compared with the human protein
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
the enzyme inactivates the neurotransmitter in the synaptic cleft
-
-
?
N-acetyl-alpha L-aspartyl-L-glutamate + H2O
N-acetyl-L-aspartate + L-glutamate
-
-
-
-
?
additional information
?
-
-
the enzyme interacts with filamin leading to internalization of PMSA into cells in the perinuclear region, overview
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
-
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
i.e. NAAG, a neurodipeptide, the enzyme acts as membrane-bound receptor being recycled through clathrin coated pits, expression regulation within cells in prostate cancer and metastasis, overview
-
-
?
N-acetyl-alpha-L-aspartyl-L-glutamate + H2O
N-acetyl-alpha-L-aspartate + L-glutamate
-
the enzyme is responsible for glutamate supply, enzyme inhibition decreases the glutamate and increases the N-acetyl-alpha-L-aspartyl-L-glutamate concentration in the brain, which can be a method to treat opioid tolerance and diminish effects of morphine withdrawal, overview
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Zn2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(phosphonomethyl)-pentanedioic acid
2-PMPA, GCPIII IC50: 94 nM, GCPII IC50: 6.74 nM
2-(3-mercaptopropyl)-pentanedioic acid
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2-MPPA, prevents morphine tolerance without affecting the acute morphine antinociception in vivo
4-[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphoryl]-methyl]-5-[[(isopropoxycarbonyl)oxy]methoxy]-5-oxopentanoic acid
the orally bioavailable prodrug affords excellent release of 2-phosphonomethylpentanedioic acid following oral administration in both mice and dog
N-[[(1S)-1-carboxy-5-(4-iodobenzamido)pentyl]carbamoyl]-L-glutamic acid
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N-[[(1S)-1-carboxy-5-([5-[3-(3-[[[2-[[[5-(2-carboxyethyl)-2-hydroxyphenyl]methyl](carboxymethyl)amino]ethyl](carboxymethyl)amino]methyl]-4-hydroxyphenyl)propanamido]pentanoyl]amino)pentyl]carbamoyl]-L-glutamic acid
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N-[[(1S)-5-([(4-bromophenyl)methyl][6-[4-(4-[4-[4-carboxy-3-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoyl]piperazin-1-yl]phenyl)piperazin-1-yl]pyridine-3-carbony]amino)-1-carboxypentyl]carbamoyl]-L-glutamic acid
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N-[[(1S)-5-[acetyl[(4-bromophenyl)methyl]amino]-1-carboxypentyl]carbamoyl]-L-glutamic acid
-
2-(phosphonomethyl)pentanedioic acid
potent inhibitor, robust neuroprotective efficacy in many neurological disease models
additional information
-
N-[N-((S)-1,3-dicarboxypropyl)carbamoyl]-S-3-iodo-L-tyrosine, i.e. DCIT, is a potent antagonist of the enzyme activity
-
additional information
-
the androgen receptor negatively regulates the enzyme expression
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00058
(2S)-2-amino-3-(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)propanoic acid
37°C, pH 7.4
0.024
N-[4-carboxy-3-(carboxymethyl)-3-hydroxybutanoyl]-L-glutamic acid
37°C, pH 7.4
0.0000059
N-[[(1S)-1-carboxy-3-methylbutyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.000000028
N-[[(1S)-1-carboxy-5-(4-iodobenzamido)pentyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.0000001
N-[[(1S)-1-carboxy-5-([5-[3-(3-[[[2-[[[5-(2-carboxyethyl)-2-hydroxyphenyl]methyl](carboxymethyl)amino]ethyl](carboxymethyl)amino]methyl]-4-hydroxyphenyl)propanamido]pentanoyl]amino)pentyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.000000049
N-[[(1S)-5-([(4-bromophenyl)methyl][6-[4-(4-[4-[4-carboxy-3-(6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoyl]piperazin-1-yl]phenyl)piperazin-1-yl]pyridine-3-carbony]amino)-1-carboxypentyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.00000066
N-[[(1S)-5-acetamido-1-carboxypentyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.00000068
N-[[(1S)-5-[acetyl[(4-bromophenyl)methyl]amino]-1-carboxypentyl]carbamoyl]-L-glutamic acid
37°C, pH 7.4
0.0000003
2-(phosphonomethyl)pentanedioic acid
pH and temperature not specified in the publication
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00000674
2-(phosphonomethyl)-pentanedioic acid
Mus musculus
2-PMPA, GCPIII IC50: 94 nM, GCPII IC50: 6.74 nM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
activity in prostate tissue homogenate in comparison to other species, overview
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pH RANGE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
especially midbrain and cerebellum, quantitative detection of GCPII content in the brain by labeling with [125I]-N-[N-((S)-1,3-dicarboxypropyl)carbamoyl]-S-3-iodo-L-tyrosine is a potent antagonist of the enzyme activity
additional information
tissue distribution of GCPIII activity and expression, overview
additional information
-
tissue distribution of GCPIII activity and expression, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme is a type II membrane glycoprotein with an intracellular segment, a transmembrane domain, and an extensive extracellular domain
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). NALD2_MOUSE
740
1
82801
Swiss-Prot
Secretory Pathway (Reliability: 3)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the enzyme is a is monomeric or dimeric type II membrane glycoprotein with an intracellular segment, a transmembrane domain, and an extensive extracellular domain
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
GCPII knockout mutant mice do not show an altered phenotype
additional information
-
GCPII knockout mutant mice do not show an altered phenotype
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
efficient one-step purification method yields purified recombinant enzyme
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene Naalad2, DNA and amino acid sequence determination and analysis, expression of GCPIII in CHO cells
a 20.7 kb gene fragment encoding exons 1-3 is subcloned and analyzed by restriction mapping
-
gene PMSA, DNA sequence variants analysis, expression regulation by PMSA enhancer, PSME, involving Ca2+, overview
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
inhibitors of glutamate carboxypeptidase II with distinct chemical scaffolds are efficacious in several neurological models wherein excess glutamatergic transmission is presumed pathogenic. These include animal models of neuropathic pain, peripheral neuropathy, stroke, amyotrophic lateral sclerosis, multiple sclerosis, schizophrenia, epilepsy, traumatic brain injury, addiction, and cognition
medicine
the enzyme is an important diagnostic marker of prostate cancer progression and a putative target for the treatment of both prostate cancer and neuronal disorders associated with glutamate excitotoxicity. For the development of novel therapeutics, mouse models are used. Differences in enzymatic activity and inhibition profile are small. Therefore, mouse glutamate carboxypeptidase II can approximate human glutamate carboxypeptidase II in drug development and testing. On the other hand, significant differences in glutamate carboxypeptidase II tissue expression must be taken into account when developing novel glutamate carboxypeptidase II-based anticancer and therapeutic methods, including targeted anticancer drug delivery systems, and when using mice as a model organism
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Ghosh, A.; Heston, W.D.
Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer
J. Cell. Biochem.
91
528-539
2004
Homo sapiens, Mus musculus, Rattus norvegicus
Bzdega, T.; Crowe, S.L.; Ramadan, E.R.; Sciarretta, K.H.; Olszewski, R.T.; Ojeifo, O.A.; Rafalski, V.A.; Wroblewska, B.; Neale, J.H.
The cloning and characterization of a second brain enzyme with NAAG peptidase activity
J. Neurochem.
89
627-635
2004
Mus musculus (Q9CZR2), Mus musculus
Guilarte, T.R.; McGlothan, J.L.; Foss, C.A.; Zhou, J.; Heston, W.D.; Kozikowski, A.P.; Pomper, M.G.
Glutamate carboxypeptidase II levels in rodent brain using [125I]DCIT quantitative autoradiography
Neurosci. Lett.
387
141-144
2005
Mus musculus, Rattus norvegicus
Aggarwal, S.; Ricklis, R.M.; Williams, S.A.; Denmeade, S.R.
Comparative study of PSMA expression in the prostate of mouse, dog, monkey, and human
Prostate
66
903-910
2006
Canis lupus familiaris, Macaca fascicularis, Homo sapiens, Macaca mulatta, Mus musculus
Kozela, E.; Wrobel, M.; Kos, T.; Wojcikowski, J.; Daniel, W.A.; Wozniak, K.M.; Slusher, B.S.; Popik, P.
2-MPPA, a selective glutamate carboxypeptidase II inhibitor, attenuates morphine tolerance but not dependence in C57/Bl mice
Psychopharmacology
183
275-284
2005
Mus musculus, Mus musculus C57/Bl
Han, L.; Picker, J.D.; Schaevitz, L.R.; Tsai, G.; Feng, J.; Jiang, Z.; Chu, H.C.; Basu, A.C.; Berger-Sweeney, J.; Coyle, J.T.
Phenotypic characterization of mice heterozygous for a null mutation of glutamate carboxypeptidase II
Synapse
63
625-635
2009
Mus musculus
Knedlik, T.; Vorlova, B.; Navratil, V.; Tykvart, J.; Sedlak, F.; Vaculin, S.; Franek, M.; Sacha, P.; Konvalinka, J.
Mouse glutamate carboxypeptidase II (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII
FEBS Open Bio
7
1362-1378
2017
Mus musculus (O35409), Mus musculus, Homo sapiens (Q04609), Homo sapiens
Majer, P.; Jankarik, A.; Krecmerova, M.; Tichy, T.; Tenora, L.; Wozniak, K.; Wu, Y.; Pommier, E.; Ferraris, D.; Rais, R.; Slusher, B.
Discovery of orally available prodrugs of the glutamate carboxypeptidase II (GCPII) inhibitor 2-phosphonomethylpentanedioic acid (2-PMPA)
J. Med. Chem.
59
2810-2819
2016
Canis lupus familiaris, Mus musculus (O35409)
EXTERNAL LINKS (specific for EC-Number 3.4.17.21)
Transporter Classification Database (TCDB): 9.B.229.1.5
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