The Experts below are selected from a list of 138 Experts worldwide ranked by ideXlab platform
Gary L. Grunewald - One of the best experts on this subject based on the ideXlab platform.
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Time-dependent inactivation of human Phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Joanne M. Caine, Gary L. Grunewald, Stuart A. Thomson, Meri Slavica, Michael J. McleishAbstract:Inhibitors of Phenylethanolamine N-methyltransferase [PNMT, the enzyme that catalyzes the final step in the biosynthesis of epinephrine (Epi)] may be of use in determining the role of Epi in the central nervous system. Here we describe the synthesis and characterization of 7-SCN tetrahydroisoquinoline as an affinity label for human PNMT.
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structural mutagenic and kinetic analysis of the binding of substrates and inhibitors of human Phenylethanolamine n methyltransferase
Journal of Medicinal Chemistry, 2005Co-Authors: Christine L Gee, Gary L. Grunewald, Frank Lin, Joel D A Tyndall, Jennifer L Martin, Michael J. McleishAbstract:The X-ray structure of human Phenylethanolamine N-methyltransferase (hPNMT) complexed. with its product, S-adenoSyl-L-homocysteine (4), and the most potent inhibitor reported to date, SK&F 64139 (7), was used to identify the residues involved in inhibitor binding. Four of these residues, Va153, Lys57, Glu219 and Asp267, were replaced, in turn, with alanine. All variants had increased K-m values for Phenylethanolamine (10), but only D267A showed a noteworthy (20-fold) decrease in its k(cat) value. Both WT hPNMT and D267A had similar k(cat) values for a rigid analogue, anti-9-amino-6-(trifluoromethyl)benzonorbornene (12), suggesting that Asp267 plays an important role in positioning the substrate but does not participate directly in catalysis. The K-i values for the binding of inhibitors such as 7 to the E219A and D267A variants increased by 2-3 orders of magnitude. Further, the inhibitors were shown to bind up to 50-fold more tightly in the presence of S-adenoSyl-(L)-methionine (3), suggesting that the binding of the latter brings about a conformational change in the enzyme.
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Inhibitors of Phenylethanolamine N-methyltransferase devoid of α2-adrenoceptor affinity
Bioorganic & medicinal chemistry letters, 2005Co-Authors: Gary L. Grunewald, Kevin R. Criscione, Cosmas O. OkoroAbstract:Abstract A series of 3-trifluoromethyl-1,2,3,4-tetrahydroisoquinolines was synthesized and evaluated for their Phenylethanolamine N-methyltransferase (PNMT) inhibitory potency and affinity for the α2-adrenoceptor. Although their PNMT inhibitory potency decreased compared with corresponding 3-methyl-, 3-hydroxymethyl- or 3-unsubstituted-THIQs, some of them showed good selectivity due to their extremely low α2-adrenoceptor affinity.
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synthesis biochemical evaluation and classical and three dimensional quantitative structure activity relationship studies of 7 substituted 1 2 3 4 tetrahydroisoquinolines and their relative affinities toward Phenylethanolamine n methyltransferase and
Journal of Medicinal Chemistry, 1999Co-Authors: Gary L. Grunewald, Vilas Hareshwar Dahanukar, Ravi K Jalluri, Kevin R. CriscioneAbstract:7-Substituted-1,2,3,4-tetrahydroisoquinolines (7-substituted-THIQs) are potent inhibitors of Phenylethanolamine N-methyltransferase (PNMT, EC 2.1.1.28), the enzyme involved in the biosynthesis of e...
Michael J. Mcleish - One of the best experts on this subject based on the ideXlab platform.
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Kinetic and pH studies on human Phenylethanolamine N-methyltransferase.
Archives of biochemistry and biophysics, 2013Co-Authors: Michael J. McleishAbstract:Phenylethanolamine N-methyltransferase (PNMT) catalyzes the conversion of norepinephrine (noradrenaline) to epinephrine (adrenaline) while, concomitantly, S-adenosyl-L-methionine (AdoMet) is converted to S-adenosyl-L-homocysteine. This reaction represents the terminal step in catecholamine biosynthesis and inhibitors of PNMT have been investigated, inter alia, as potential antihypertensive agents. At various times the kinetic mechanism of PNMT has been reported to operate by a random mechanism, an ordered mechanism in which norepinephrine binds first, and an ordered mechanism in which AdoMet binds first. Here we report the results of initial velocity studies on human PNMT in the absence and presence of product and dead end inhibitors. These, coupled with isothermal titration calorimetry and fluorescence binding experiments, clearly shown that hPNMT operates by an ordered sequential mechanism in which AdoMet binds first. Although the logV pH-profile was not well defined, plots of logV/K versus pH for AdoMet and Phenylethanolamine, as well as the pKi versus pH for the inhibitor, SK&F 29661, were all bell-shaped indicating that a protonated and an unprotonated group are required for catalysis.
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Time-dependent inactivation of human Phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydroisoquinoline
Bioorganic & medicinal chemistry letters, 2009Co-Authors: Joanne M. Caine, Gary L. Grunewald, Stuart A. Thomson, Meri Slavica, Michael J. McleishAbstract:Inhibitors of Phenylethanolamine N-methyltransferase [PNMT, the enzyme that catalyzes the final step in the biosynthesis of epinephrine (Epi)] may be of use in determining the role of Epi in the central nervous system. Here we describe the synthesis and characterization of 7-SCN tetrahydroisoquinoline as an affinity label for human PNMT.
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structural mutagenic and kinetic analysis of the binding of substrates and inhibitors of human Phenylethanolamine n methyltransferase
Journal of Medicinal Chemistry, 2005Co-Authors: Christine L Gee, Gary L. Grunewald, Frank Lin, Joel D A Tyndall, Jennifer L Martin, Michael J. McleishAbstract:The X-ray structure of human Phenylethanolamine N-methyltransferase (hPNMT) complexed. with its product, S-adenoSyl-L-homocysteine (4), and the most potent inhibitor reported to date, SK&F 64139 (7), was used to identify the residues involved in inhibitor binding. Four of these residues, Va153, Lys57, Glu219 and Asp267, were replaced, in turn, with alanine. All variants had increased K-m values for Phenylethanolamine (10), but only D267A showed a noteworthy (20-fold) decrease in its k(cat) value. Both WT hPNMT and D267A had similar k(cat) values for a rigid analogue, anti-9-amino-6-(trifluoromethyl)benzonorbornene (12), suggesting that Asp267 plays an important role in positioning the substrate but does not participate directly in catalysis. The K-i values for the binding of inhibitors such as 7 to the E219A and D267A variants increased by 2-3 orders of magnitude. Further, the inhibitors were shown to bind up to 50-fold more tightly in the presence of S-adenoSyl-(L)-methionine (3), suggesting that the binding of the latter brings about a conformational change in the enzyme.
Vern L. Schramm - One of the best experts on this subject based on the ideXlab platform.
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Transition-State Analogues of Phenylethanolamine N-Methyltransferase.
Journal of the American Chemical Society, 2020Co-Authors: Niusha Mahmoodi, Rajesh K. Harijan, Vern L. SchrammAbstract:Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine f...
Hiro Furukawa - One of the best experts on this subject based on the ideXlab platform.
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Subunit Arrangement and Phenylethanolamine Binding in
2016Co-Authors: Glun/glunb Nmda Receptors, Erkan Karakas, Noriko Simorowski, Hiro FurukawaAbstract:Since it was unexpectedly discovered that the anti-hypertensive agent, ifenprodil, has neuroprotective activity through effects to N-methyl-D-aspartate (NMDA) receptors1, enormous efforts have been made to understand the mechanism of action and to develop improved therapeutic compounds based on this knowledge2–4. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function5. These receptors form heteromeric ion channels and become activated upon concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion channel activity is allosterically regulated by binding of small compounds to the amino terminal domain (ATD) in a subtype specific manner. Ifenprodil and related Phenylethanolamine compounds, which specifically inhibit GluN1/GluN2B NMDA receptors6,7, have been intensely studied for their potential use in treatment of various neurological disorders and diseases including depression, Alzheimer’s disease and Parkinson’s disease2,4. Despite great enthusiasm, mechanisms underlying recognition of Phenylethanolamines and the ATD-mediated allosteric inhibition remain limited due to lack of structural information. Here we report that the GluN1 and GluN2B ATDs form heterodimer and that Phenylethanolamine binds at the GluN1-GluN2
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subunit arrangement and Phenylethanolamine binding in glun1 glun2b nmda receptors
Nature, 2011Co-Authors: Erkan Karakas, Noriko Simorowski, Hiro FurukawaAbstract:Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related Phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlying the recognition of Phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that Phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for Phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.
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Subunit arrangement and Phenylethanolamine binding in GluN1/GluN2B NMDA receptors
Nature, 2011Co-Authors: Erkan Karakas, Noriko Simorowski, Hiro FurukawaAbstract:Since it was discovered that the anti-hypertensive agent ifenprodil has neuroprotective activity through its effects on NMDA (N-methyl-D-aspartate) receptors, a determined effort has been made to understand the mechanism of action and to develop improved therapeutic compounds on the basis of this knowledge. Neurotransmission mediated by NMDA receptors is essential for basic brain development and function. These receptors form heteromeric ion channels and become activated after concurrent binding of glycine and glutamate to the GluN1 and GluN2 subunits, respectively. A functional hallmark of NMDA receptors is that their ion-channel activity is allosterically regulated by binding of small compounds to the amino-terminal domain (ATD) in a subtype-specific manner. Ifenprodil and related Phenylethanolamine compounds, which specifically inhibit GluN1 and GluN2B NMDA receptors, have been intensely studied for their potential use in the treatment of various neurological disorders and diseases, including depression, Alzheimer's disease and Parkinson's disease. Despite considerable enthusiasm, mechanisms underlying the recognition of Phenylethanolamines and ATD-mediated allosteric inhibition remain limited owing to a lack of structural information. Here we report that the GluN1 and GluN2B ATDs form a heterodimer and that Phenylethanolamine binds at the interface between GluN1 and GluN2B, rather than within the GluN2B cleft. The crystal structure of the heterodimer formed between the GluN1b ATD from Xenopus laevis and the GluN2B ATD from Rattus norvegicus shows a highly distinct pattern of subunit arrangement that is different from the arrangements observed in homodimeric non-NMDA receptors and reveals the molecular determinants for Phenylethanolamine binding. Restriction of domain movement in the bi-lobed structure of the GluN2B ATD, by engineering of an inter-subunit disulphide bond, markedly decreases sensitivity to ifenprodil, indicating that conformational freedom in the GluN2B ATD is essential for ifenprodil-mediated allosteric inhibition of NMDA receptors. These findings pave the way for improving the design of subtype-specific compounds with therapeutic value for neurological disorders and diseases.
Niusha Mahmoodi - One of the best experts on this subject based on the ideXlab platform.
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Transition-State Analogues of Phenylethanolamine N-Methyltransferase.
Journal of the American Chemical Society, 2020Co-Authors: Niusha Mahmoodi, Rajesh K. Harijan, Vern L. SchrammAbstract:Phenylethanolamine N-methyltransferase (PNMT) is a critical enzyme in catecholamine synthesis. It transfers the methyl group of S-adenosylmethionine (SAM) to catalyze the synthesis of epinephrine f...
