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Glutamate Carboxypeptidase

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...
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
Pavel Majer, Andrej Jančařík, Marcela Krečmerová, Tomáš Tichý, Lukáš Tenora, Krystyna Wozniak, Ying Wu, Elie Pommier, Dana Ferraris, Rana Rais, Barbara S Slusher
2-Phosphonomethylpentanedioic acid (1, 2-PMPA) is a potent inhibitor of glutamate carboxypeptidase II which has demonstrated robust neuroprotective efficacy in many neurological disease models. However, 1 is highly polar containing a phosphonate and two carboxylates, severely limiting its oral bioavailability. We strategized to mask the polar groups via a prodrug approach, increasing the likelihood of passive oral absorption. Our initial strategy was to cover the phosphonate with hydrophobic moieties such as pivaloyloxymethyl (POM) and isopropyloxycarbonyloxymethyl (POC) while keeping the α- and γ-carboxylates unsubstituted...
March 24, 2016: Journal of Medicinal Chemistry
Cindy J Choy, Clifford E Berkman
The rapid dilution of the enzyme-inhibitor complex assay to monitor the recovery of enzyme activity is a well-established assay to determine the reversibility of inhibition. Our laboratory has previously employed this method to ascertain the reversibility of known glutamate carboxypeptidase II (GCPII)-targeting agents. Due to the tedious and time-consuming nature of the assay, we sought to develop a facile method to determine the reversibility of well-characterized GCPII inhibitors using bio-layer interferometry (BLI)...
December 2016: Journal of Enzyme Inhibition and Medicinal Chemistry
Yanjie Liu, Emilisa Frirdich, Jennifer A Taylor, Anson C K Chan, Kris M Blair, Jenny Vermeulen, Reuben Ha, Michael E P Murphy, Nina R Salama, Erin C Gaynor, Martin E Tanner
Helicobacter pylori and Campylobacter jejuni are human pathogens and causative agents of gastric ulcers/cancer and gastroenteritis, respectively. Recent studies have uncovered a series of proteases that are responsible for maintaining the helical shape of these organisms. The H. pylori metalloprotease Csd4 and its C. jejuni homologue Pgp1 cleave the amide bond between meso-diaminopimelate and iso-d-glutamic acid in truncated peptidoglycan side chains. Deletion of either csd4 or pgp1 results in bacteria with a straight rod phenotype, a reduced ability to move in viscous media, and reduced pathogenicity...
April 15, 2016: ACS Chemical Biology
Shaik Mohammad Naushad, Parvathaneni Shree Divyya, M Janaki Ramaiah, Balraj Alex Stanley, S Prasanna Lakshmi, J Vishnupriya, Vijay Kumar Kutala
In view of documented evidence showing glutamate carboxypeptidase II (GCPII) inhibitors as promising anti-cancer agents, certain variants of GCPII modulate breast and prostate cancer risk, and we developed an artificial neural network (ANN) model of GCPII variants and ascertained the risk associated with eight genetic variants of GCPII. In parallel, an in silico model was developed to substantiate the ANN simulations. The ANN model with modified sigmoid function was used for disease prediction, whereas the hyperbolic tangent function was used to predict folate hydrolase 1 (FOLH1) and prostate specific membrane antigen (PSMA) expression...
November 2015: Cancer Genetics
Zora Novakova, Jiri Cerny, Cindy J Choy, Jessie R Nedrow, Joeseph K Choi, Jacek Lubkowski, Clifford E Berkman, Cyril Barinka
UNLABELLED: Inhibitors targeting human glutamate carboxypeptidase II (GCPII) typically consist of a P1' glutamate-derived binding module, which warrants the high affinity and specificity, linked to an effector function that is positioned within the entrance funnel of the enzyme. Here we present a comprehensive structural and computational study aimed at dissecting the importance of the effector function for GCPII binding and affinity. To this end we determined crystal structures of human GCPII in complex with a series of phosphoramidate-based inhibitors harboring effector functions of diverse physicochemical characteristics...
January 2016: FEBS Journal
Sihyun Youn, Kyung Im Kim, Jakub Ptacek, Kiwon Ok, Zora Novakova, YunHye Kim, JaeHyung Koo, Cyril Barinka, Youngjoo Byun
Glutamate carboxypeptidase II (GCPII) is a zinc metalloprotease on the surface of astrocytes which cleaves N-acetylaspartylglutamate to release N-acetylaspartate and glutamate. GCPII inhibitors can decrease glutamate concentration and play a protective role against apoptosis or degradation of brain neurons. Herein, we report the synthesis and structural analysis of novel carborane-based GCPII inhibitors. We determined the X-ray crystal structure of GCPII in complex with a carborane-containing inhibitor at 1...
November 15, 2015: Bioorganic & Medicinal Chemistry Letters
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