tailieunhanh - Báo cáo khoa học: Endogenous tetrahydroisoquinolines associated with Parkinson’s disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines

N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cere-brospinal fluid of patients with Parkinson’s disease. We show here that 6,7-dihydroxylated tetrahydroisoquinolines such asN-methyl-norsalsolinol inhibit tyrosine hydroxylase, the key enzyme in dopamine synthesis, by imitating the mechanisms of catecholamine feedback regulation. | ỊFEBS Journal Endogenous tetrahydroisoquinolines associated with Parkinson s disease mimic the feedback inhibition of tyrosine hydroxylase by catecholamines Joachim Scholz1 2 Karen Toska3 z Alexander Luborzewski1 Astrid Maass4 Volker Schunemann5 Jan Haavik3 and Andreas Moser1 1 Neurochemistry Research Group Department of Neurology University of Lubeck Germany 2 NeuralPlasticity Research Group Department of Anesthesia and CriticalCare Massachusetts GeneralHospitaland Harvard Medical School Charlestown MA USA 3 Department of Biomedicine Section of Biochemistry and Molecular Biology University of Bergen Norway 4 Fraunhofer-Institute for Algorithms and Scientific Computing SCAI Sankt Augustin Germany 5 Department of Physics TechnicalUniversity Kaiserslautern Germany Keywords enzyme stability feedback inhibition Parkinson s disease tetrahydroisoquinolines tyrosine hydroxylase Correspondence J. Scholz NeuralPlasticity Research Group Department of Anesthesia and Critical Care Massachusetts GeneralHospitaland Harvard Medical School 149 13th Street Room 4309 Charlestown MA 02129 USA Fax 1 617 7243632 Tel 1 617 7243623 E-mail These authors contributed equally to this work Received 14 November 2007 revised 23 January 2008 accepted 28 February 2008 doi N-methyl-norsalsolinol and related tetrahydroisoquinolines accumulate in the nigrostriatal system of the human brain and are increased in the cerebrospinal fluid of patients with Parkinson s disease. We show here that 6 7-dihydroxylated tetrahydroisoquinolines such as N-methyl-norsalsolinol inhibit tyrosine hydroxylase the key enzyme in dopamine synthesis by imitating the mechanisms of catecholamine feedback regulation. Docked into a model of the enzyme s active site 6 7-dihydroxylated tetrahydroisoquinolines were ligated directly to the iron in the catalytic center occupying the same position as the catecholamine inhibitor dopamine. In this position the ligands .