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Glutamate Carboxypeptidase

Takahiro Nonaka, Toshihiko Yamada, Tatsuhiro Ishimura, Daiying Zuo, John R Moffett, Joseph H Neale, Tatsuo Yamamoto
N-acetylaspartylglutamate (NAAG) is the third most prevalent and widely distributed neurotransmitter in the mammalian nervous system. NAAG activates a group II metabotropic glutamate receptor (mGluR3) and is inactivated by an extracellular enzyme, glutamate carboxypeptidase II (GCPII) in vivo. Inhibitors of this enzyme are analgesic in animal models of inflammatory, neuropathic and bone cancer pain. NAAG and GCPII are present in the locus coeruleus, a center for the descending noradrenergic inhibitory pain system...
January 2017: Molecular Pain
Kyota Yasuda, Sarah F Clatterbuck-Soper, Meredith E Jackrel, James Shorter, Stavroula Mili
Cytoplasmic inclusions of the RNA-binding protein fused in sarcoma (FUS) represent one type of membraneless ribonucleoprotein compartment. Formation of FUS inclusions is promoted by amyotrophic lateral sclerosis (ALS)-linked mutations, but the cellular functions affected upon inclusion formation are poorly defined. In this study, we find that FUS inclusions lead to the mislocalization of specific RNAs from fibroblast cell protrusions and neuronal axons. This is mediated by recruitment of kinesin-1 mRNA and protein within FUS inclusions, leading to a loss of detyrosinated glutamate (Glu)-microtubules (MTs; Glu-MTs) and an inability to support the localization of RNAs at protrusions...
April 3, 2017: Journal of Cell Biology
Rafal T Olszewski, Karolina J Janczura, Tomasz Bzdega, Elise K Der, Faustino Venzor, Brennen O'Rourke, Timothy J Hark, Kirsten E Craddock, Shankar Balasubramanian, Charbel Moussa, Joseph H Neale
Glutamate carboxypeptidase II (GCPII) inactivates the peptide neurotransmitter N-acetylaspartylglutamate (NAAG) following synaptic release. Inhibitors of GCPII increase extracellular NAAG levels and are efficacious in animal models of clinical disorders via NAAG activation of a group II metabotropic glutamate receptor. mGluR2 and mGluR3 knock-out (ko) mice were used to test the hypothesis that mGluR3 mediates the activity of GCPII inhibitors ZJ43 and 2-PMPA in animal models of memory and memory loss. Short- (1...
March 11, 2017: Neurochemical Research
Callum Hicks, Ryan A Gregg, Sunil U Nayak, Lee Anne Cannella, Giana J Schena, Christopher S Tallarida, Allen B Reitz, Garry R Smith, Scott M Rawls
RATIONALE: Metabotropic glutamate 2 and 3 (mGluR2/3) receptors are implicated in drug addiction as they limit excessive glutamate release during relapse. N-acetylaspartylglutamate (NAAG) is an endogenous mGluR2/3 agonist that is inactivated by the glutamate carboxypeptidase II (GCPII) enzyme. GCPII inhibitors, and NAAG itself, attenuate cocaine-seeking behaviors. However, their effects on the synthetic cathinone 3,4-methylenedioxypyrovalerone (MDPV) have not been examined. OBJECTIVES: We determined whether withdrawal following repeated MDPV administration alters GCPII expression in corticolimbic regions...
March 1, 2017: Psychopharmacology
Hui-Yuan Wu, Peng Wei, James I Morgan
Proteins may undergo a type of posttranslational modification - polyglutamylation, where a glutamate residue is enzymatically linked to the γ-carboxyl group of a glutamate in the primary sequence of proteins and additional glutamates are then sequentially added via α-carboxyl-linkages to the growing glutamate side chain. Nna1 (a.k.a. CCP1) defines the 6-member cytosolic carboxypeptidase (CCP) family that metabolizes polyglutamate side chain and its loss results in neurodegeneration and male infertility. Whereas most CCPs catalyze hydrolysis of α-carboxyl-linked glutamates, CCP5 uniquely metabolizes the γ-carboxyl linked, branch point glutamate...
January 27, 2017: Scientific Reports
Jae-Hye Lee, Hyun-Soo Cho, Jeong-Ju Lee, Soo Young Jun, Jun-Ho Ahn, Ju-Sik Min, Ji-Yong Yoon, Min-Hyuk Choi, Su-Jin Jeon, Jung Hwa Lim, Cho-Rok Jung, Dae-Soo Kim, Hyun-Taek Kim, Valentina M Factor, Yun-Han Lee, Snorri S Thorgeirsson, Cheol-Hee Kim, Nam-Soon Kim
Tumor metastasis is the leading cause of cancer death. In the metastatic process, EMT is a unique phenotypic change that plays an important role in cell invasion and changes in cell morphology. Despite the clinical significance, the mechanism underlying tumor metastasis is still poorly understood. Here we report a novel mechanism by which secreted plasma glutamate carboxypeptidase(PGCP) negatively involves Wnt/β-catenin signaling by DKK4 regulation in liver cancer metastasis. Pathway analysis of the RNA sequencing data showed that PGCP knockdown in liver cancer cell lines enriched the functions of cell migration, motility and mesenchymal cell differentiation...
November 29, 2016: Oncotarget
Min Woo Lee, Rira Seo, Yu Jeong Lee, Ju Hye Bae, Jung-Kwon Park, Joung-Hahn Yoon, Jei Wan Lee, Ho Won Jung
An Arabidopsis thaliana ALTERED MERISTEM PROGRAM1 (AtAMP1), which encodes a putative glutamate carboxypeptidase, not only controls shoot apical meristem development, but also is involved in tolerance response to abiotic stresses. Here, we introduce a novel mutant; named amp1-32 that is a phenocopier to previously isolated different amp1 mutant alleles. Interestingly, tiny leaves were continuously developed at the bottom of pre-emerged leaves in the amp1-32. The amp1-32 mutant was less sensitive to heat shock treatment lasting for 3 h, whereas disease symptoms were severely developed in the mutant after Pseudomonas syringae infection...
October 12, 2016: Biochemical and Biophysical Research Communications
Thorsten Derlin, Johannes Thiele, Desiree Weiberg, James T Thackeray, Klaus Püschel, Hans-Jürgen Wester, Lukas Aguirre Dávila, Axel Larena-Avellaneda, Günter Daum, Frank M Bengel, Udo Schumacher
OBJECTIVE: Intraplaque neovascularization contributes to the progression and rupture of atherosclerotic lesions. Glutamate carboxypeptidase II (GCPII) is strongly expressed by endothelial cells of tumor neovasculature and plays a major role in hypoxia-induced neovascularization in rodent models of benign diseases. We hypothesized that GCPII expression may play a role in intraplaque neovascularization and may represent a target for imaging of atherosclerotic lesions. The aim of this study was to determine frequency, pattern, and clinical correlates of vessel wall uptake of a (68)Ga-GCPII ligand for positron emission tomographic imaging...
September 8, 2016: Arteriosclerosis, Thrombosis, and Vascular Biology
Rana Rais, Weiwei Jiang, Huihong Zhai, Krystyna M Wozniak, Marigo Stathis, Kristen R Hollinger, Ajit G Thomas, Camilo Rojas, James J Vornov, Michael Marohn, Xuhang Li, Barbara S Slusher
Recent gene-profiling analyses showed significant upregulation of the folate hydrolase (FOLH1) gene in the affected intestinal mucosa of patients with inflammatory bowel disease (IBD). The FOLH1 gene encodes a type II transmembrane glycoprotein termed glutamate carboxypeptidase II (GCPII). To establish that the previously reported increased gene expression was functional, we quantified the glutamate carboxypeptidase enzymatic activity in 31 surgical specimens and report a robust 2.8- to 41-fold increase in enzymatic activity in the affected intestinal mucosa of IBD patients compared with an uninvolved area in the same patients or intestinal mucosa from healthy controls...
August 4, 2016: JCI Insight
James C Evans, Meenakshi Malhotra, John F Cryan, Caitriona M O'Driscoll
Prostate specific membrane antigen (PSMA) otherwise known as glutamate carboxypeptidase II (GCPII) is a membrane bound protein that is highly expressed in prostate cancer and in the neovasculature of a wide variety of tumours including glioblastomas, breast and bladder cancers. This protein is also involved in a variety of neurological diseases including schizophrenia and ALS. In recent years, there has been a surge in the development of both diagnostics and therapeutics that take advantage of the expression and activity of PSMA/GCPII...
November 2016: British Journal of Pharmacology
Danbee Ha, So Jin Bing, Ginnae Ahn, Jinhee Kim, Jinhee Cho, Areum Kim, Kalahe H I N M Herath, Hak Sun Yu, Sangmee Ahn Jo, Ik-Hyun Cho, Youngheun Jee
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory disease in the murine central nervous system (CNS) and recapitulates the clinical and pathological features of human multiple sclerosis (MS). Glutamate carboxipeptidase II (GCPII), an enzyme expressed exclusively on astrocytes, is known to affect the disease progression of various neurological disorders by producing glutamate. Despite several findings indicating possible link between glutamate and MS/EAE, however, the involvement of astrocyte or GCPII on glutamate excitotoxicity has not received much attention in MS/EAE...
September 2016: FEBS Journal
Shaik Mohammad Naushad, M Janaki Ramaiah, Balraj Alex Stanley, S Prasanna Lakshmi, J Vishnu Priya, Tajamul Hussain, Salman A Alrokayan, Vijay Kumar Kutala
To develop a potential inhibitor for glutamate carboxypeptidase II (GCPII) effective against all the eight common genetic variants reported, PyMOL molecular visualization system was used to generate models of variants using the crystal structure of GCPII i.e. 2OOT as a template. High-throughput virtual screening of 29 compounds revealed differential efficacy across the eight genetic variants (pIC50: 4.70 to 10.22). Pharmacophore analysis and quantitative structure-activity relationship (QSAR) studies revealed a urea-based N-acetyl aspartyl glutamate (NAAG) analogue as more potent inhibitor, which was effective across all the genetic variants of GCPII as evidenced by glide scores (-4...
October 7, 2016: Journal of Theoretical Biology
Rebecca E Conway, Camilo Rojas, Jesse Alt, Zora Nováková, Spencer M Richardson, Tori C Rodrick, Julio L Fuentes, Noah H Richardson, Jonathan Attalla, Samantha Stewart, Beshoy Fahmy, Cyril Barinka, Mallika Ghosh, Linda H Shapiro, Barbara S Slusher
Prostate-specific membrane antigen (PSMA) is a membrane-bound glutamate carboxypeptidase expressed in a number of tissues. PSMA participates in various biological functions depending on the substrate available in the particular tissue; in the brain, PSMA cleaves the abundant neuropeptide N-acetyl-aspartyl-glutamate to regulate release of key neurotransmitters, while intestinal PSMA cleaves polyglutamated peptides to supply dietary folate. PSMA expression is also progressively upregulated in prostate cancer where it correlates with tumor progression as well as in tumor vasculature, where it regulates angiogenesis...
October 2016: Angiogenesis
Zhi Zhang, Bassam Bassam, Ajit G Thomas, Monica Williams, Jinhuan Liu, Elizabeth Nance, Camilo Rojas, Barbara S Slusher, Sujatha Kannan
Astrocyte dysfunction and excessive activation of glutamatergic systems have been implicated in a number of neurologic disorders, including periventricular leukomalacia (PVL) and cerebral palsy (CP). However, the role of chorioamnionitis on glutamate homeostasis in the fetal and neonatal brains is not clearly understood. We have previously shown that intrauterine endotoxin administration results in intense microglial 'activation' and increased pro-inflammatory cytokines in the periventricular region (PVR) of the neonatal rabbit brain...
October 2016: Neurobiology of Disease
Fraser Lough, John D Perry, Stephen P Stanforth, John R Dean
A novel method for the determination of benzoic acid has been employed to identify carboxypeptidase activities in clinically relevant pathogens. Benzoic acid was determined after chemical derivatization by gas chromatography-mass spectrometry (GC-MS). N-Benzoyl amino acid substrates were evaluated for the detection of carboxypeptidase activities in a number of clinical pathogens. Upon enzymatic hydrolysis of these substrates, benzoic acid was produced which was detected by extraction from the liquid culture supernatant, derivatization as the trimethylsilyl ester, with subsequent analysis by GC-MS...
May 23, 2016: Analytical Letters
Michal Navrátil, Jan Tykvart, Jiří Schimer, Petr Pachl, Václav Navrátil, Tibor András Rokob, Klára Hlouchová, Lubomír Rulíšek, Jan Konvalinka
UNLABELLED: Glutamate carboxypeptidase III (GCPIII) is best known as a homologue of glutamate carboxypeptidase II [GCPII; also known as prostate-specific membrane antigen (PSMA)], a protease involved in neurological disorders and overexpressed in a number of solid cancers. However, mouse GCPIII was recently shown to cleave β-citrylglutamate (BCG), suggesting that these two closely related enzymes have distinct functions. To develop a tool to dissect, evaluate and quantify the activities of human GCPII and GCPIII, we analysed the catalytic efficiencies of these enzymes towards three physiological substrates...
July 2016: FEBS Journal
Darshana Mirgal, Kanjaksha Ghosh, Jagadish Mahanta, Prafulla Dutta, Shrimati Shetty
BACKGROUND: Recent studies in experimental mice have shown that mild deficiency of methylenetetrahydrofolate reductase (MTHFR) enzyme confers protection against malaria, thus providing an important basis for the hypothesis that MTHFR polymorphism, i.e. C677T, might have been subjected to selection pressure against malaria. The present study was undertaken in a malaria endemic region in North East India to assess whether a similar selection advantage exists for other genes in folate metabolism pathway...
May 2016: Transactions of the Royal Society of Tropical Medicine and Hygiene
Yang Cao, Yang Gao, Siyi Xu, Jingang Bao, Yingying Lin, Xingguang Luo, Yong Wang, Qizhong Luo, Jiyao Jiang, Joseph H Neale, Chunlong Zhong
BACKGROUND: Glutamate carboxypeptidase II (GCPII) inactivates the peptide co-transmitter N-acetylaspartylglutamate following synaptic release. Inhibition of GCPII elevates extracellular levels of the peptide, inhibits glutamate release and is neuroprotective in an animal model of traumatic brain injury. GCPII gene knockout mice were used to examine the cellular mechanisms underlying the neuroprotective efficacy of this transmitter system. RESULTS: Following controlled cortical impact injury, GCPII knockout (KO) mice exhibited reduced TUNEL-positive nuclei in the contusion margin of the cerebral cortex relative to wild type mice...
April 18, 2016: BMC Neuroscience
Zora Novakova, Krystyna Wozniak, Andrej Jancarik, Rana Rais, Ying Wu, Jiri Pavlicek, Dana Ferraris, Barbora Havlinova, Jakub Ptacek, Jan Vavra, Niyada Hin, Camilo Rojas, Pavel Majer, Barbara S Slusher, Takashi Tsukamoto, Cyril Barinka
Inhibition of glutamate carboxypeptidase II (GCPII) is effective in preclinical models of neurological disorders associated with excessive activation of glutamatergic systems. Here we report synthesis, structural characterization, and biological activity of new hydroxamic acid-based inhibitors with nanomolar affinity for human GCPII. Crystal structures of GCPII/hydroxamate complexes revealed an unprecedented binding mode in which the putative P1' glutarate occupies the spacious entrance funnel rather than the conserved glutamate-binding S1' pocket...
May 26, 2016: Journal of Medicinal Chemistry
Weiqiao Zhang, Zhijie Zhang, Liping Wu, Yongming Qiu, Yingying Lin
BACKGROUND: Ischemia stroke is a destructive cerebrovascular disease and a major cause of death and lifelong neurological disability. N-Acetyl-l-aspartyl-l-glutamate (NAAG) is a neurotransmitter in the mammalian brain and involves a variety of physiological and pathological functions including ischemia brain injury. Full understanding of the functions of NAAG peptidase (GCPII) in the pathogenesis of ischemia brain injury is extremely valuable for effective therapies to ischemia stroke...
July 2016: Journal of Stroke and Cerebrovascular Diseases: the Official Journal of National Stroke Association
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