The Experts below are selected from a list of 213 Experts worldwide ranked by ideXlab platform
Nancy A Muma - One of the best experts on this subject based on the ideXlab platform.
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receptor stimulated transamidation induces activation of rac1 and cdc42 and the regulation of dendritic spines
Neuropharmacology, 2017Co-Authors: Zhen Mi, Khushboo Kapadia, Tuda Si, Qian Li, Nancy A MumaAbstract:Abstract Regulation of dendritic spines is an important component of synaptic function and plasticity whereas dendritic spine dysregulation is related to several psychiatric and neurological diseases. In the present study, we tested the hypothesis that serotonin (5-HT)2A/2C receptor-induced Rho family transamidation and activation regulates dendritic spine morphology and that activation of multiple types of receptors can induce transglutaminase (TGase)-catalyzed transamidation of small G proteins. We previously reported a novel 5-HT2A receptor downstream effector, TGase-catalyzed serotonylation of the small G protein Rac1 in A1A1v cells, a rat embryonic cortical cell line. We now extend these findings to rat primary cortical cultures which develop dendritic spines; stimulation of 5-HT2A/2C receptors increased transamidation of Rac1 and Cdc42, but not RhoA. Inhibition of TGases significantly decreased transamidation and activation of Rac1 and Cdc42, suggesting that transamidation led to their activation. In primary cortical cultures, stimulation of 5-HT2A/2C receptors by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) caused a transient dendritic spine enlargement, which was blocked by TGase inhibition. Stimulation of both 5-HT2A and 5-HT2C receptors contributed to DOI-induced Rac1 transamidation in primary cortical cultures as demonstrated by selective antagonists. Furthermore, stimulation of muscarinic acetylcholine receptors and NMDA receptors also increased TGase-catalyzed Rac1 activation in SH-SY5Y cells and N2a cells, respectively. Receptor-stimulated TGase-catalyzed transamidation of Rac1 occurs at Q61, a site previously reported to be important in the inactivation of Rac1. These studies demonstrate that TGase-catalyzed transamidation and activation of small G proteins results from stimulation of multiple types of receptors and this novel signaling pathway can regulate dendritic spine morphology and plasticity.
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serotonylation and transamidation of other monoamines
ACS Chemical Neuroscience, 2015Co-Authors: Nancy A Muma, Zhen MiAbstract:Although serotonin was discovered over 65 years ago, it has been only within the past decade that serotonin was found to be involved in a covalent post-translational modification to proteins. The enzyme transglutaminase catalyzes the transamidation of serotonin to a protein-bound glutamine residue; the amino group of serotonin is covalently bound to the gamma carboxamide of glutamine. The term serotonylation is used to describe this transamidation reaction to serotonin. Not only can serotonin be a substrate for transamidation to proteins but also other monoamine neurotransmitters are substrates including histamine, dopamine, and noradrenaline. The term monoaminylation has been coined to describe the transamidation of monoamines to protein substrates. Small G proteins have emerged as the most common substrate for monoaminylation and are activated by this post-translational modification. Fibronectin and cytoskeletal proteins are also substrates for monoaminylation. Serotonylation and monoaminylation are inv...
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Phospholipase C, Ca2+, and calmodulin signaling are required for 5-HT2A receptor-mediated transamidation of Rac1 by transglutaminase.
Psychopharmacology, 2010Co-Authors: Nichole L Dudek, Qian Li, Nancy A MumaAbstract:Serotonin and especially serotonin 2A (5-HT(2A)) receptor signaling are important in the etiology and treatment of schizophrenia and affective disorders. We previously reported a novel 5-HT(2A) receptor effector, increased transglutaminase (TGase)-catalyzed transamidation, and activation of the small G protein Rac1 in A1A1v cells, a rat embryonic cortical cell line. In this study, we explore the signaling pathway involved in 5-HT(2A) receptor-mediated Rac1 transamidation. A1A1v cells were pretreated with pharmacological inhibitors of phospholipase C (PLC) or calmodulin (CaM), and then stimulated by the 5-HT(2A) receptor agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI). Intracellular Ca(2+) concentration and TGase-modified Rac1 transamidation were monitored. The effect of manipulation of intracellular Ca(2+) by a Ca(2+) ionophore or a chelating agent on Rac1 transamidation was also evaluated. In cells pretreated with a PLC inhibitor U73122, DOI-stimulated increases in the intracellular Ca(2+) concentration and TGase-modified Rac1 were significantly attenuated as compared to those pretreated with U73343, an inactive analog. The membrane-permeant Ca(2+) chelator, BAPTA-AM strongly reduced TGase-catalyzed Rac1 transamidation upon DOI stimulation. Conversely, the Ca(2+) ionophore ionomycin, at a concentration that induced an elevation of cytosolic Ca(2+) to a level comparable to cells treated with DOI, produced an increase in TGase-modified Rac1 without 5-HT(2A) receptor activation. Moreover, the CaM inhibitor W-7, significantly decreased Rac1 transamidation in a dose-dependent manner in DOI-treated cells. These results indicate that 5-HT(2A) receptor-coupled PLC activation and subsequent Ca(2+) and CaM signaling are necessary for TGase-catalyzed Rac1 transamidation, and an increase in intracellular Ca(2+) is sufficient to induce Rac1 transamidation.
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transglutaminase catalyzed transamidation a novel mechanism for rac1 activation by 5 hydroxytryptamine2a receptor stimulation
Journal of Pharmacology and Experimental Therapeutics, 2008Co-Authors: Nichole L Dudek, Tarun B Patel, Nancy A MumaAbstract:Transglutaminase (TGase)-induced activation of small G proteins via 5-hydroxytryptamine (HT)2A receptor signaling leads to platelet aggregation ( Cell 115: 851–862, 2003). We hypothesize that stimulation of 5-HT2A receptors in neurons activates TGase, resulting in transamidation of serotonin to a small G protein, Rac1, thereby constitutively activating Rac1. Using immunoprecipitation and immunoblotting, we show that, in rat cortical cell line A1A1v, serotonin increases TGase-catalyzed transamidation of Rac1. This transamidation occurs in both undifferentiated and differentiated cells. Treatment with a 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-iodoamphetamine, but not the 5-HT1A receptor agonist 5-hydroxy-2-dipropylamino tetralin, increases transamidation of Rac1 by TGase. In A1A1v cells, 5-HT2A receptors mediate the transamidation reaction because expression of 5-HT2C receptors was not detectable and the selective 5-HT2A receptor antagonist blocked transamidation. Time course studies demonstrate that transamidation of Rac1 is significantly elevated after 5 and 15 min of serotonin treatment, but returns it to control levels after 30 min. The activity of Rac1 is also transiently increased following serotonin stimulation. Inhibition of TGase by cystamine or small interfering RNA reduces TGase modification of Rac1, and cystamine also prevents Rac1 activation. Serotonin itself is bound to Rac1 by TGase following 5-HT2A receptor stimulation as demonstrated by coimmunoprecipitation experiments and a dose-dependent decrease of serotonin-associated Rac1 by cystamine. These data support the hypothesis that Rac1 activity is transiently increased due to TGase-catalyzed transamidation of serotonin to Rac1 via stimulation of 5-HT2A receptors. Activation of Rac1 via TGase is a novel effector and second messenger of the 5-HT2A receptor-signaling cascade in neurons.
Thierry Gefflaut - One of the best experts on this subject based on the ideXlab platform.
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Enantioselective Synthesis of d - and l -α-Amino Acids by Enzymatic Transamination Using Glutamine as Smart Amine Donor
Advanced Synthesis and Catalysis, 2019Co-Authors: Egon Heuson, Franck Charmantray, Jean-louis Petit, Véronique De Berardinis, Thierry GefflautAbstract:Enzymatic Transamination is a useful method for the green and highly enantioselective synthesis of chiral amines and non‐canonical amino acids which are of major importance as intermediates in medicinal chemistry. However, Transamination reactions are usually reversible and synthetic applications of transaminases often require the implementation of an equilibrium shift strategy. Herein, we report a highly effective approach using glutamine as smart amine donor. This amino acid is converted upon Transamination into 2‐oxoglutaramate which undergoes a fast cyclisation displacing the Transamination equilibrium. We have developed a new activity assay in order to identify transaminases from biodiversity able to convert various α‐keto acids into valuable amino acids of l‐ or d‐series in the presence of glutamine as amine donor. Discovered transaminases were then used to prepare in high yield and with high enantioselectivity three amino acids of pharmaceutical importance, homophenylalanine, homoalanine and tert‐leucine by simply using a nearly stoichiometric amount of glutamine as amine donor.
Neil K. Garg - One of the best experts on this subject based on the ideXlab platform.
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nickel catalyzed transamidation of aliphatic amide derivatives
Chemical Science, 2017Co-Authors: Jacob E Dander, Emma L Baker, Neil K. GargAbstract:Transamidation, or the conversion of one amide to another, is a long-standing challenge in organic synthesis. Although notable progress has been made in the transamidation of primary amides, the transamidation of secondary amides has remained underdeveloped, especially when considering aliphatic substrates. Herein, we report a two-step approach to achieve the transamidation of secondary aliphatic amides, which relies on non-precious metal catalysis. The method involves initial Boc-functionalization of secondary amide substrates to weaken the amide C–N bond. Subsequent treatment with a nickel catalyst, in the presence of an appropriate amine coupling partner, then delivers the net transamidated products. The transformation proceeds in synthetically useful yields across a range of substrates. A series of competition experiments delineate selectivity patterns that should influence future synthetic design. Moreover, the transamidation of Boc-activated secondary amide derivatives bearing epimerizable stereocenters underscores the mildness and synthetic utility of this methodology. This study provides the most general solution to the classic problem of secondary amide transamidation reported to date.
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a two step approach to achieve secondary amide transamidation enabled by nickel catalysis
Nature Communications, 2016Co-Authors: Emma L Baker, Michael M Yamano, Sarah M Anthony, Yujing Zhou, Neil K. GargAbstract:A long-standing challenge in synthetic chemistry is the development of the transamidation reaction. This process, which involves the conversion of one amide to another, is typically plagued by unfavourable kinetic and thermodynamic factors. Although some advances have been made with regard to the transamidation of primary amide substrates, secondary amide transamidation has remained elusive. Here we present a simple two-step approach that allows for the elusive overall transformation to take place using non-precious metal catalysis. The methodology proceeds under exceptionally mild reaction conditions and is tolerant of amino-acid-derived nucleophiles. In addition to overcoming the classic problem of secondary amide transamidation, our studies expand the growing repertoire of new transformations mediated by base metal catalysis.
Yian Shi - One of the best experts on this subject based on the ideXlab platform.
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Progress in asymmetric biomimetic Transamination of carbonyl compounds
Chemical Society Reviews, 2015Co-Authors: Ying Xie, Hongjie Pan, Mao Liu, Xiao Xiao, Yian ShiAbstract:Transamination of α-keto acids with transaminases and pyridoxamine phosphate is an important process to form optically active α-amino acids in biological systems. Various biomimetic Transamination systems have been developed for carbonyl compounds including α-keto acid derivatives, fluoroalkyl ketones, and unactivated ketones with chiral vitamin B6 analogues, artificial transaminase mimics, chiral nitrogen sources, and chiral catalysts. This review provides a brief summary of this area.
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the effect of benzyl amine on the efficiency of the base catalyzed Transamination of α keto esters
Tetrahedron, 2012Co-Authors: Fazhen Xue, Xiao Xiao, Yian Shi, Haining WangAbstract:Abstract This paper describes the effect of benzyl amine on the base-catalyzed Transamination of α-keto esters. Among various benzyl amines examined, o -HOC 6 H 4 CH 2 NH 2 was found to be highly effective for the reaction, affording a wide variety of α-amino esters in good yields. The o -OH group of the benzyl amine facilitates the Transamination process likely via H-bond. Moderate enantiomeric excess was obtained for α-amino ester when a quinine derived catalyst was used.
Jorge Tamarit-rodriguez - One of the best experts on this subject based on the ideXlab platform.
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Branched-chain 2-oxoacids Transamination increases “GABA-shunt” metabolism and insulin secretion in isolated islets
Biochemical Journal, 2009Co-Authors: Javier Pizarro-delgado, Inés Hernández-fisac, Rafael Martín-del-río, Jorge Tamarit-rodriguezAbstract:We have previously shown that oxo-4-methylpentanoate promotes islet GABA metabolism and stimulates insulin secretion. The main aim of this work was to explore the participation of the Transamination of branched-chain 2-oxoacids in these processes with the aid of several inhibitors of this enzyme activity. No correlation was found between the Transamination of branched-chain 2-oxoacids in islet homogenates and insulin secretion. However, in vivo Transamination rates correlated better with the secretion capacity of the different branched-chain 2-oxoacids. Gabapentin, a specific inhibitor of the cytosolic isozyme, showed greater potential to decrease the in vitro Transamination rates of oxo-3-methylbutyrate and oxo-3-methylpentanoate than those of oxo-4-methylpentanoate and oxohexanoate; this correlated with its capacity to decrease insulin secretion. 4-Methylvaleric acid very strongly inhibited the Transamination of all the branched-chain 2-oxoacids and blocked their capacity to decrease islet GABA and to stimulate insulin secretion. 70 mM KCl stimulated islet GABA release, subsequently decreasing its tissue concentration. This “non metabolic” decrease of GABA suppressed the second phase of insulin secretion triggered by oxo-4-methylpentanoate and oxohexanoate. Oxo-4-methylpentanoate and oxo-3-methylpentanoate suppressed dose-dependent 2-oxoglutarate dehydrogenase activity in islet homogenates. In conclusion: 1. The Transamination of branched-chain 2-oxoacids is more important to the stimulation of insulin secretion than their catabolism. 2. Transamination decreases islet GABA concentrations by promoting GABA metabolism. 3. Inhibition of 2-oxoglutarate dehydrogenase by branched-chain 2-oxoacids may increase metabolic flux in the “GABA-shunt” at the expense of reduced TCA cycle flux.
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Branched-chain 2-oxoacid Transamination increases GABA-shunt metabolism and insulin secretion in isolated islets.
Biochemical Journal, 2009Co-Authors: Javier Pizarro-delgado, Inés Hernández-fisac, Rafael Martín-del-río, Jorge Tamarit-rodriguezAbstract:We have previously shown that oxo-4-methylpentanoate promotes islet GABA (gamma-aminobutyric acid) metabolism and stimulates insulin secretion. The main aim of this work was to explore the participation of the Transamination of branched-chain 2-oxoacids in these processes with the aid of several inhibitors of this enzyme activity. No correlation was found between the Transamination of branched-chain 2-oxoacids in islet homogenates and insulin secretion. However, in vivo Transamination rates correlated better with the secretion capacity of the different branched-chain 2-oxoacids. Gabapentin, a specific inhibitor of the cytosolic isoenzyme, showed greater potential to decrease the in vitro Transamination rates of oxo-3-methylbutyrate and oxo-3-methylpentanoate than those of oxo-4-methylpentanoate and oxohexanoate; this correlated with its capacity to decrease insulin secretion. 4-Methylvaleric acid very strongly inhibited the Transamination of all the branched-chain 2-oxoacids and blocked their capacity to decrease islet GABA and to stimulate insulin secretion. KCl at 70 mM at stimulated islet GABA release, subsequently decreasing its tissue concentration. This 'non-metabolic' decrease of GABA suppressed the second phase of insulin secretion triggered by oxo-4-methylpentanoate and oxohexanoate. Oxo-4-methylpentanoate and oxo-3-methylpentanoate suppressed dose-dependent 2-oxoglutarate dehydrogenase activity in islet homogenates. In conclusion, the Transamination of branchedchain 2-oxoacids is more important to the stimulation of insulin secretion than their catabolism, and Transamination decreases islet GABA concentrations by promoting GABA metabolism. Also, inhibition of 2-oxoglutarate dehydrogenase by branched-chain 2-oxoacids may increase metabolic flux in the 'GABA-shunt' at the expense of reduced tricarboxylic acid cycle flux.
