Characterisation of the Tailoring and Transport Enzymes Involved in the Microcystin Biosynthesis Pathway
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The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1]. -
Activation of Group I Metabotropic Glutamate Receptors Reduces Neuronal Apoptosis but Increases Necrotic Cell Death in Vitro
Cell Death and Differentiation (2000) 7, 470 ± 476 ã 2000 Macmillan Publishers Ltd All rights reserved 1350-9047/00 $15.00 www.nature.com/cdd Activation of group I metabotropic glutamate receptors reduces neuronal apoptosis but increases necrotic cell death in vitro JW Allen1,2, SM Knoblach1,3 and AI Faden*,1,3,4 hydroxyphenylglycine; DHPG, dihydroxyphenylglycine; MK801, dizocilpine; LDH, lactate dehydrogenase; MCPG, -methyl-4- 1 Institute for Cognitive and Computational Sciences, Georgetown University carboxyphenylglycine; mGluR, metabotropic glutamate receptors; Medical Center, Washington, DC 20007, USA OGD, oxygen-glucose deprivation; TBI, traumatic brain injury 2 Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA 3 Department of Neuroscience, Georgetown University Medical Center, Washington, DC 20007, USA Introduction 4 Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA Activation of both ionotropic and metabotropic glutamate * Corresponding author: AI Faden, EP-04 Research Building, 3970 Reservoir receptors has been implicated in the pathophysiology of Road, N.W. Washington, DC 20007, USA. Tel: (202) 687 0492; Fax: (202) 687 stroke and CNS trauma. It has been well established that 0617; E-mail: [email protected] blockade of ionotropic glutamate receptors provides neuro- protection in vitro and in vivo.1±5 Recent studies have suggested that metabotropic glutamate receptors (mGluR) Received 23.7.99; revised 19.1.00; accepted 7.2.00 are also activated following traumatic brain injury (TBI)6±9 or Edited by FD Miller cerebral ischemia,10 or in vitro neuronal trauma7,9 or ischemia,11,12 leading to neuroprotection or exacerbation depending upon the mGluR subtype activated. -
Designing Peptidomimetics
CORE Metadata, citation and similar papers at core.ac.uk Provided by UPCommons. Portal del coneixement obert de la UPC DESIGNING PEPTIDOMIMETICS Juan J. Perez Dept. of Chemical Engineering ETS d’Enginyeria Industrial Av. Diagonal, 647 08028 Barcelona, Spain 1 Abstract The concept of a peptidomimetic was coined about forty years ago. Since then, an enormous effort and interest has been devoted to mimic the properties of peptides with small molecules or pseudopeptides. The present report aims to review different approaches described in the past to succeed in this goal. Basically, there are two different approaches to design peptidomimetics: a medicinal chemistry approach, where parts of the peptide are successively replaced by non-peptide moieties until getting a non-peptide molecule and a biophysical approach, where a hypothesis of the bioactive form of the peptide is sketched and peptidomimetics are designed based on hanging the appropriate chemical moieties on diverse scaffolds. Although both approaches have been used in the past, the former has been more widely used to design peptidomimetics of secretory peptides, whereas the latter is nowadays getting momentum with the recent interest in designing protein-protein interaction inhibitors. The present report summarizes the relevance of the information gathered from structure-activity studies, together with a short review on the strategies used to design new peptide analogs and surrogates. In a following section there is a short discussion on the characterization of the bioactive conformation of a peptide, to continue describing the process of designing conformationally constrained analogs producing first and second generation peptidomimetics. Finally, there is a section devoted to review the use of organic scaffolds to design peptidomimetics based on the information available on the bioactive conformation of the peptide. -
Buyers' Guide
Buyers’ Guide S119 Buyers’ Guide Suppliers’ Contact Details Amersham Biosciences UK Limited The Menarini Group Amersham Place www.menarini.com Little Chalfont Buckinghamshire HP7 9NA Moravek Biochemicals UK 577 Mercury Lane www5.amershambiosciences.com Brea Ca 92821 Avanti Polar Lipids Inc USA 700 Industrial Park Drive www.moravek.com Alabaster AL 35007 Roche Pharmaceuticals USA F. Hoffmann-La Roche Ltd www.avantilipids.com Pharmaceuticals Division Grenzacherstrasse 124 Bachem Bioscience Inc. CH-4070 Basel 3700 Horizon Drive Switzerland King of Prussia Telephone þ 41-61-688 1111 PA 19406 Unites States Telefax þ 41-61-691 9391 www.bachem.org www.roche.com Boehringer Ingelheim Ltd Ellesfield Avenue SIGMA Chemicals/Sigma-Aldrich Bracknell P.O. Box 14508 Berks RG12 8YS St. Louis, MO 63178-9916 UK USA www.boehringer-ingelheim.co.uk www.sigma-aldrich.com Calbiochem Tocris Cookson Ltd. EMD Biosciences, Inc. Northpoint, Fourth Way 10394 Pacific Center Court Avonmouth San Diego Bristol CA 92121 BS11 8TA USA UK www.emdbiosciences.com www.tocris.com S120 Buyers’ Guide Compound Supplier Buyers’ Guide a-methyl-5-HT a-Methyl-5-hydroxytryptamine Tocris ab-meATP ab-methylene-adenosine 5’-triphosphate Sigma-Aldrich bg-meATP bg-methylene-adenosine 5’-triphosphate Sigma-Aldrich (-)-(S)-BAYK8664 (-)-(S)-methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluromethylphenyl)-pyridine-5-carboxylate Sigma-Aldrich, Tocris (+)7-OH-DPAT (+)-7-hydroxy-2-aminopropylaminotetralin Sigma-Aldrich a-dendrotoxin Sigma-Aldrich (RS)PPG (R,S)-4-phosphonophenylglycine Tocris (S)-3,4-DCPG -
Polyketide Synthase Gene Coupled to the Peptide Synthetase Module Involved in the Biosynthesis of the Cyclic Heptapeptide Microcystinl
J. Biochem. 127, 779-789(2000) Polyketide Synthase Gene Coupled to the Peptide Synthetase Module Involved in the Biosynthesis of the Cyclic Heptapeptide Microcystinl Tomoyasu Nishizawa, Akiko Ueda, Munehiko Asayama,* Kiyonaga Fujii,•õ Ken-ichi Harada,i Kozo Ochi,•ö and Makoto Shirai*,•˜,2 * Division of Biotechnology, School ofAgriculture, Ibaraki University Ami , Ibaraki 300-0393; •õFaculty of Pharmacy, M eija University, Tempaku , Nagoya 468-8503, •öNational Food Research Institute, Tsukuba, Ibaraki 305-8642; and •˜ Gene Research Center, Ibaraki University, Ann, Ibaraki 300-0393 Received January 17, 2000; accepted February 11, 2000 The peptide synthetase gene operon, which consists of encyA, mcyB, and mcyC, for the activation and incorporation of the five amino acid constituents of microcystin has been identified [T. Nishizawa et al. (1999) J. Biochem. 126, 520-529] . By sequencing an addi tional 34 kb of DNA from microcystin-producing Microcystis aeruginosa K-139 , we identifi ed the residual microcystin synthetase gene operon, which consists of mcyD, mcyE, meyF, and mcyG, in the opposite orientation to the mcyABC operon. McyD consisted of two polyketide synthase modules, and McyE contained a polyketide synthase module at the N-terminus and a peptide synthetase module at the C-terminus. McyF was found to exhibit similarity to amino acid racemase. McyG consisted of a peptide synthetase mod ule at the N-terminus and a polyketide synthase at the C-terminus. The microcystin syn thetase gene cluster was conserved in another microcystin-producing strain, Microcystis sp. S-70, which produces Microcystin-LR, -RR, and -YR. Insertional mutagenesis of mcyA, mcyD, or meyE in Microcystis sp. -
Amino Acids by G.C.BARRETT
1 Amino Acids By G.C.BARRETT 1 Introduction The chemistry and biochemistry of the amino acids as represented in the 1992 literature, is covered in this Chapter. The usual policy for this Specialist Periodical Report has been continued, with almost exclusive attention in this Chapter, to the literature covering the natural occurrence, chemistry, and analysis methodology for the amino acids. Routine literature covering the natural distribution of well-known amino acids is excluded. The discussion offered is brief for most of the papers cited, so that adequate commentary can be offered for papers describing significant advances in synthetic methodology and mechanistically-interesting chemistry. Patent literature is almost wholly excluded but this is easily reached through Section 34 of Chemical Abstracts. It is worth noting that the relative number of patents carried in Section 34 of Chemical Abstracts is increasing (e.g. Section 34 of Chem-Abs., 1992, Vol. 116, Issue No. 11 contains 45 patent abstracts, 77 abstracts of papers and reviews), reflecting the perception that amino acids and peptides are capable of returning rich commercial rewards due to their important physiological roles and consequent pharmaceutical status. However, there is no slowing of the flow of journal papers and secondary literature, as far as the amino acids are concerned. The coverage in this Chapter is arranged into sections as used in all previous Volumes of this Specialist Periodical Report, and major Journals and Chemical Abstracts (to Volume 118, issue 11) have -
Interrupted Adenylation Domains: Unique Bifunctional Enzymes Involved in Nonribosomal Peptide Biosynthesis
Natural Product Reports Interrupted adenylation domains: unique bifunctional enzymes involved in nonribosomal peptide biosynthesis Journal: Natural Product Reports Manuscript ID: NP-REV-09-2014-000120.R1 Article Type: Highlight Date Submitted by the Author: 12-Jan-2015 Complete List of Authors: Labby, Kristin; Beloit College, Chemistry Watsula, Stoyan; University of Michigan, Medicinal Chemistry Garneau-Tsodikova, Sylvie; University of Kentucky, Pharmaceutical Sciences Page 1 of 11NPR Natural Product Reports Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx HIGHLIGHT Interrupted adenylation domains: unique bifunctional enzymes involved in nonribosomal peptide biosynthesis Kristin J. Labby, a Stoyan G. Watsula,b and Sylvie Garneau-Tsodikova* c Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX 5 DOI: 10.1039/b000000x Covering up to 2014 Nonribosomal peptides (NRPs) account for a large portion of drugs and drug leads currently available in the pharmaceutical industry. They are one of two main families of natural products biosynthesized on megaenzyme assembly-lines composed of multiple modules that are, in general, each comprised of three 10 core domains and on occasion of accompanying auxiliary domains. The core adenylation (A) domains are known to delineate the identity of the specific chemical components to be incorporated into the growing NRPs. Previously believed to be inactive, A domains interrupted by auxiliary enzymes have recently been proven to be active and capable of performing two distinct chemical reactions. This highlight summarizes current knowledge on A domains and presents the various interrupted A domains found in a number of 15 nonribosomal peptide synthetase (NRPS) assembly-lines, their predicted or proven dual functions, and their potential for manipulation and engineering for chemoenzymatic synthesis of new pharmaceutical agents with increased potency. -
Evidence for Metabotropic Glutamate Receptor Activation in the Induction of Depolarization-Induced Suppression of Inhibition in Hippocampal CA1
The Journal of Neuroscience, July 1, 1998, 18(13):4870–4882 Evidence for Metabotropic Glutamate Receptor Activation in the Induction of Depolarization-Induced Suppression of Inhibition in Hippocampal CA1 Wade Morishita, Sergei A. Kirov, and Bradley E. Alger Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland 21201 Depolarization-induced suppression of inhibition (DSI) is a tran- (1S,3R)-ACPD-induced IPSC suppression and markedly re- sient reduction of GABAA receptor-mediated IPSCs that is duced DSI, whereas group III antagonists had no effect on DSI. mediated by a retrograde signal from principal cells to interneu- Many other similarities between DSI and the (1S,3R)-ACPD- rons. Using whole-cell recordings, we tested the hypothesis induced suppression of IPSCs also were found. Our data sug- that mGluRs are involved in the DSI process in hippocampal gest that a glutamate-like substance released from pyramidal CA1, as has been proposed for cerebellar DSI. Group II mGluR cells could mediate CA1 DSI by reducing GABA release from agonists failed to affect either evoked monosynaptic IPSCs or interneurons via the activation of group I mGluRs. DSI, and forskolin, which blocks cerebellar DSI, did not affect CA1 DSI. Group I and group III mGluR agonists reduced IPSCs, Key words: IPSP; GABA; retrograde signal; voltage clamp; but only group I agonists occluded DSI. (S)-MCPG blocked mGluR; synaptic inhibition Depolarization-induced suppression of inhibition (DSI) is a phe- decrease cAMP production (Conn et al., 1994), which can reduce nomenon seen in both hippocampal CA1 pyramidal cells (Pitler GABA release (Capogna et al., 1995). -
Microglial Glutathione and Glutamate: Regulation Mechanisms
Microglial glutathione and glutamate: Regulation mechanisms Victoria Anne Honey Fry UCL Institute of Neurology A thesis submitted for the degree of Doctor of Philosophy (Ph.D.) 1 I, Victoria Fry, confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. 2 Abstract Microglia, the immune cells of the central nervous system (CNS), are important in the protection of the CNS, but may be implicated in the pathogenesis of neuroinflammatory disease. Upon activation, microglia produce reactive oxygen and nitrogen species; intracellular antioxidants are therefore likely to be important in their self-defence. Here, it was confirmed that cultured microglia contain high levels of glutathione, the predominant intracellular antioxidant in mammalian cells. The activation of microglia with lipopolysaccharide (LPS) or LPS + interferon- was shown to affect their glutathione levels. GSH levels in primary microglia and those of the BV-2 cell line increased upon activation, whilst levels in N9 microglial cells decreased. - Microglial glutathione synthesis is dependent upon cystine uptake via the xc transporter, which exchanges cystine and glutamate. Glutamate is an excitatory neurotransmitter whose extracellular concentration is tightly regulated by excitatory amino acid transporters, as high levels cause toxicity to neurones and other CNS cell types through overstimulation of - glutamate receptors or by causing reversal of xc transporters. Following exposure to LPS, increased extracellular glutamate and increased levels of messenger ribonucleic acid - (mRNA) for xCT, the specific subunit of xc , were observed in BV-2 and primary microglial cells, suggesting upregulated GSH synthesis. -
1 Activation of the Same Mglur5 Receptors in the Amygdala Causes Divergent Effects 2 on Specific Versus Indiscriminate Fear 3
1 Activation of the same mGluR5 receptors in the amygdala causes divergent effects 2 on specific versus indiscriminate fear 3 4 Mohammed Mostafizur Rahman1,2,#, Sonal Kedia1,#, Giselle Fernandes1#, Sumantra 5 Chattarji1,2,3* 6 7 1National Centre for Biological Sciences, Tata Institute of Fundamental Research, 8 Bangalore 560065, India 9 10 2Centre for Brain Development and Repair, Institute for Stem Cell Biology and 11 Regenerative Medicine, Bangalore 560065, India 12 13 3Centre for Integrative Physiology, Deanery of Biomedical Sciences, University of 14 Edinburgh, Hugh Robson Building, George Square, Edinburgh EH89XD, UK 15 16 17 * Corresponding Author: Prof. Sumantra Chattarji 18 Centre for Brain Development and Repair, Institute for 19 Stem Cell Biology and Regenerative Medicine and 20 National Centre for Biological Sciences 21 Bangalore 560065, INDIA 22 E-Mail: [email protected] 23 # Equal contribution 24 1 25 Abstract 26 27 Although mGluR5-antagonists prevent fear and anxiety, little is known about how the 28 same receptor in the amygdala gives rise to both. Combining in vitro and in vivo 29 activation of mGluR5 in rats, we identify specific changes in intrinsic excitability and 30 synaptic plasticity in basolateral amygdala neurons that give rise to temporally distinct 31 and mutually exclusive effects on fear-related behaviors. The immediate impact of 32 mGluR5 activation is to produce anxiety manifested as indiscriminate fear of both tone 33 and context. Surprisingly, this state does not interfere with the proper encoding of tone- 34 shock associations that eventually lead to enhanced cue-specific fear. These results 35 provide a new framework for dissecting the functional impact of amygdalar mGluR- 36 plasticity on fear versus anxiety in health and disease. -
Identification and Analysis of Hepatitis C Virus NS3 Helicase Inhibitors Using Nucleic Acid Binding Assays Sourav Mukherjee1, Alicia M
Published online 27 June 2012 Nucleic Acids Research, 2012, Vol. 40, No. 17 8607–8621 doi:10.1093/nar/gks623 Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays Sourav Mukherjee1, Alicia M. Hanson1, William R. Shadrick1, Jean Ndjomou1, Noreena L. Sweeney1, John J. Hernandez1, Diana Bartczak1, Kelin Li2, Kevin J. Frankowski2, Julie A. Heck3, Leggy A. Arnold1, Frank J. Schoenen2 and David N. Frick1,* 1Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, 2University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Dr., Lawrence, KS 66047 and 3Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA Received March 26, 2012; Revised May 30, 2012; Accepted June 4, 2012 Downloaded from ABSTRACT INTRODUCTION Typical assays used to discover and analyze small All cells and viruses need helicases to read, replicate and molecules that inhibit the hepatitis C virus (HCV) repair their genomes. Cellular organisms encode NS3 helicase yield few hits and are often con- numerous specialized helicases that unwind DNA, RNA http://nar.oxfordjournals.org/ founded by compound interference. Oligonucleotide or displace nucleic acid binding proteins in reactions binding assays are examined here as an alternative. fuelled by ATP hydrolysis. Small molecules that inhibit After comparing fluorescence polarization (FP), helicases would therefore be valuable as molecular homogeneous time-resolved fluorescence (HTRFÕ; probes to understand the biological role of a particular Cisbio) and AlphaScreenÕ (Perkin Elmer) assays, helicase, or as antibiotic or antiviral drugs (1,2). For an FP-based assay was chosen to screen Sigma’s example, several compounds that inhibit a helicase Library of Pharmacologically Active Compounds encoded by herpes simplex virus (HSV) are potent drugs in animal models (3,4). -
Dendritic Spines Elongate After Stimulation of Group 1 Metabotropic Glutamate Receptors in Cultured Hippocampal Neurons
Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons Peter W. Vanderklish*† and Gerald M. Edelman*‡ *Department of Neurobiology, The Scripps Research Institute and ‡The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, CA 92037 Contributed by Gerald M. Edelman, December 18, 2001 Changes in the morphology of dendritic spines are correlated with length. As with activation of NMDA receptors (12), stimulation synaptic plasticity and may relate mechanistically to its expression of group 1 mGluRs also leads to postsynaptic protein synthesis and stabilization. Recent work has shown that spine length can be (13–15). Calcium mobilization and protein synthesis triggered by altered by manipulations that affect intracellular calcium, and group 1 mGluRs are involved both in LTD (16, 17) and in the spine length is abnormal in genetic conditions affecting protein priming of hippocampal synapses for subsequent induction of synthesis in neurons. We have investigated how ligands of group stable LTP (15). 1 metabotropic glutamate receptors (mGluRs) affect spine shape; Our working hypothesis is that group 1 mGluR activation may stimulation of these receptors leads both to calcium release from regulate spine shape through mechanisms that are also involved intracellular stores and to dendritic protein synthesis. Thirty- in the production of synaptic plasticity. We assayed the effects of minute incubation of cultured hippocampal slices and dissociated treating hippocampal neurons with the group 1 mGluR-selective neurons with the selective group 1 mGluR agonist (S)-3,5-dihy- agonist (S)-3,5-dihydroxyphenylglycine (DHPG) on the length droxyphenylglycine (DHPG) induced a significant increase in the of dendritic spines.