Tolstykh T

References (6)

Title : Selective blockade of the hydrolysis of the endocannabinoid 2-arachidonoylglycerol impairs learning and memory performance while producing antinociceptive activity in rodents - Griebel_2015_Sci.Rep_5_7642
Author(s) : Griebel G , Pichat P , Beeske S , Leroy T , Redon N , Jacquet A , Francon D , Bert L , Even L , Lopez-Grancha M , Tolstykh T , Sun F , Yu Q , Brittain S , Arlt H , He T , Zhang B , Wiederschain D , Bertrand T , Houtmann J , Rak A , Vallee F , Michot N , Auge F , Menet V , Bergis OE , George P , Avenet P , Mikol V , Didier M , Escoubet J
Ref : Sci Rep , 5 :7642 , 2015
Abstract : Monoacylglycerol lipase (MAGL) represents a primary degradation enzyme of the endogenous cannabinoid (eCB), 2-arachidonoyglycerol (2-AG). This study reports a potent covalent MAGL inhibitor, SAR127303. The compound behaves as a selective and competitive inhibitor of mouse and human MAGL, which potently elevates hippocampal levels of 2-AG in mice. In vivo, SAR127303 produces antinociceptive effects in assays of inflammatory and visceral pain. In addition, the drug alters learning performance in several assays related to episodic, working and spatial memory. Moreover, long term potentiation (LTP) of CA1 synaptic transmission and acetylcholine release in the hippocampus, two hallmarks of memory function, are both decreased by SAR127303. Although inactive in acute seizure tests, repeated administration of SAR127303 delays the acquisition and decreases kindled seizures in mice, indicating that the drug slows down epileptogenesis, a finding deserving further investigation to evaluate the potential of MAGL inhibitors as antiepileptics. However, the observation that 2-AG hydrolysis blockade alters learning and memory performance, suggests that such drugs may have limited value as therapeutic agents.
ESTHER : Griebel_2015_Sci.Rep_5_7642
PubMedSearch : Griebel_2015_Sci.Rep_5_7642
PubMedID: 25560837
Gene_locus related to this paper: mouse-ABHD6

Title : Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661 - Furman_2011_Antiviral.Res_91_120
Author(s) : Furman PA , Murakami E , Niu C , Lam AM , Espiritu C , Bansal S , Bao H , Tolstykh T , Micolochick Steuer H , Keilman M , Zennou V , Bourne N , Veselenak RL , Chang W , Ross BS , Du J , Otto MJ , Sofia MJ
Ref : Antiviral Res , 91 :120 , 2011
Abstract : PSI-353661, a phosphoramidate prodrug of 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype 1a and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5'-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O(6)-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration.
ESTHER : Furman_2011_Antiviral.Res_91_120
PubMedSearch : Furman_2011_Antiviral.Res_91_120
PubMedID: 21600932

Title : Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977 - Murakami_2010_J.Biol.Chem_285_34337
Author(s) : Murakami E , Tolstykh T , Bao H , Niu C , Steuer HM , Bao D , Chang W , Espiritu C , Bansal S , Lam AM , Otto MJ , Sofia MJ , Furman PA
Ref : Journal of Biological Chemistry , 285 :34337 , 2010
Abstract : A phosphoramidate prodrug of 2'-deoxy-2'-alpha-fluoro-beta-C-methyluridine-5'-monophosphate, PSI-7851, demonstrates potent anti-hepatitis C virus (HCV) activity both in vitro and in vivo. PSI-7851 is a mixture of two diastereoisomers, PSI-7976 and PSI-7977, with PSI-7977 being the more active inhibitor of HCV RNA replication in the HCV replicon assay. To inhibit the HCV NS5B RNA-dependent RNA polymerase, PSI-7851 must be metabolized to the active triphosphate form. The first step, hydrolysis of the carboxyl ester by human cathepsin A (CatA) and/or carboxylesterase 1 (CES1), is a stereospecific reaction. Western blot analysis showed that CatA and CES1 are both expressed in primary human hepatocytes. However, expression of CES1 is undetectable in clone A replicon cells. Studies with inhibitors of CatA and/or CES1 indicated that CatA is primarily responsible for hydrolysis of the carboxyl ester in clone A cells, although in primary human hepatocytes, both CatA and CES1 contribute to the hydrolysis. Hydrolysis of the ester is followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the spontaneous elimination of phenol and the production of an alaninyl phosphate metabolite, PSI-352707, which is common to both isomers. The removal of the amino acid moiety of PSI-352707 is catalyzed by histidine triad nucleotide-binding protein 1 (Hint1) to give the 5'-monophosphate form, PSI-7411. siRNA-mediated Hint1 knockdown studies further indicate that Hint1 is, at least in part, responsible for converting PSI-352707 to PSI-7411. PSI-7411 is then consecutively phosphorylated to the diphosphate, PSI-7410, and to the active triphosphate metabolite, PSI-7409, by UMP-CMP kinase and nucleoside diphosphate kinase, respectively.
ESTHER : Murakami_2010_J.Biol.Chem_285_34337
PubMedSearch : Murakami_2010_J.Biol.Chem_285_34337
PubMedID: 20801890

Title : Carboxyl methylation regulates phosphoprotein phosphatase 2A by controlling the association of regulatory B subunits - Tolstykh_2000_EMBO.J_19_5682
Author(s) : Tolstykh T , Lee J , Vafai S , Stock JB
Ref : EMBO Journal , 19 :5682 , 2000
Abstract : Phosphoprotein phosphatase 2A (PP2A) is a major phosphoserine/threonine protein phosphatase in all eukaryotes. It has been isolated as a heterotrimeric holoenzyme composed of a 65 kDa A subunit, which serves as a scaffold for the association of the 36 kDa catalytic C subunit, and a variety of B subunits that control phosphatase specificity. The C subunit is reversibly methyl esterified by specific methyltransferase and methylesterase enzymes at a completely conserved C-terminal leucine residue. Here we show that methylation plays an essential role in promoting PP2A holoenzyme assembly and that demethylation has an opposing effect. Changes in methylation indirectly regulate PP2A phosphatase activity by controlling the binding of regulatory B subunits to AC dimers.
ESTHER : Tolstykh_2000_EMBO.J_19_5682
PubMedSearch : Tolstykh_2000_EMBO.J_19_5682
PubMedID: 11060019
Gene_locus related to this paper: human-PPME1

Title : Carboxyl methylation of the phosphoprotein phosphatase 2A catalytic subunit promotes its functional association with regulatory subunits in vivo - Wu_2000_EMBO.J_19_5672
Author(s) : Wu J , Tolstykh T , Lee J , Boyd K , Stock JB , Broach JR
Ref : EMBO Journal , 19 :5672 , 2000
Abstract : The phosphoprotein phosphatase 2A (PP2A) catalytic subunit contains a methyl ester on its C-terminus, which in mammalian cells is added by a specific carboxyl methyltransferase and removed by a specific carboxyl methylesterase. We have identified genes in yeast that show significant homology to human carboxyl methyltransferase and methylesterase. Extracts of wild-type yeast cells contain carboxyl methyltransferase activity, while extracts of strains deleted for one of the methyltransferase genes, PPM1, lack all activity. Mutation of PPM1 partially disrupts the PP2A holoenzyme in vivo and ppm1 mutations exhibit synthetic lethality with mutations in genes encoding the B or B' regulatory subunit. Inactivation of PPM1 or overexpression of PPE1, the yeast gene homologous to bovine methylesterase, yields phenotypes similar to those observed after inactivation of either regulatory subunit. These phenotypes can be reversed by overexpression of the B regulatory subunit. These results demonstrate that Ppm1 is the sole PP2A methyltransferase in yeast and that its activity is required for the integrity of the PP2A holoenzyme.
ESTHER : Wu_2000_EMBO.J_19_5672
PubMedSearch : Wu_2000_EMBO.J_19_5672
PubMedID: 11060018
Gene_locus related to this paper: yeast-ppme1

Title : A specific protein carboxyl methylesterase that demethylates phosphoprotein phosphatase 2A in bovine brain - Lee_1996_Proc.Natl.Acad.Sci.U.S.A_93_6043
Author(s) : Lee J , Chen Y , Tolstykh T , Stock J
Ref : Proc Natl Acad Sci U S A , 93 :6043 , 1996
Abstract : Phosphoprotein phosphatase 2A (PP2A) is one of the four major protein serine/threonine phosphatases found in all eukaryotic cells. We have shown that the 36-kDa catalytic subunit of PP2A is carboxyl methylated in eukaryotic cells, and we have previously identified and purified a novel methyltransferase (MTase) that is responsible for this modification. Here, we describe a novel protein carboxyl methyl-esterase (MEase) from bovine brain that demethylates PP2A. The enzyme has been purified to homogeneity as a monomeric 46-kDa soluble protein. The MEase is highly specific for PP2A. It does not catalyze the demethylation of other protein or peptide methylesters. Moreover, MEase activity is dramatically inhibited by nanomolar concentrations of okadaic acid, a specific inhibitor of PP2A. From these results, we conclude that PP2A methylation is controlled by two specific enzymes, a MTase and a MEase. Since PP2A methylation is highly conserved in eukaryotes ranging from human to yeast, it is likely that this system plays an important role in phosphatase regulation.
ESTHER : Lee_1996_Proc.Natl.Acad.Sci.U.S.A_93_6043
PubMedSearch : Lee_1996_Proc.Natl.Acad.Sci.U.S.A_93_6043
PubMedID: 8650216
Gene_locus related to this paper: human-PPME1