NDLI: Molecular Recognition at the Active Site of Catechol-O-methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors

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Molecular Recognition at the Active Site of Catechol-O-methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors

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Molecular Recognition at the Active Site of Catechol-O-methyltransferase (COMT): Adenine Replacements in Bisubstrate Inhibitors

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Rudolph, Markus G. Paulini, Ralph Lerner, Christian Ellermann, Manuel Jakob-roetne, Roland Diederich, François Roth, Doris Ehler, Andreas Schlatter, Daniel Schweizer, W. Bernd Borroni, Edilio
Description	Author Affiliation: Ellermann M ( Laboratorium für Organische Chemie, ETH-Zürich, Wolfgang-Pauli-Strasse 10, 8093 Zürich, Switzerland.)
Abstract	L-Dopa, the standard therapeutic for Parkinson’s disease, is inactivated by the enzyme catechol-O-methyltransferase (COMT). COMT catalyzes the transfer of an activated methyl group from S-adenosylmethionine (SAM) to its catechol substrates, such as L-dopa, in the presence of magnesium ions. The molecular recognition properties of the SAM-binding site of COMT have been investigated only sparsely. Here, we explore this site by structural alterations of the adenine moiety of bisubstrate inhibitors. The molecular recognition of adenine is of special interest due to the great abundance and importance of this nucleobase in biological systems. Novel bisubstrate inhibitors with adenine replacements were developed by structure-based design and synthesized using a nucleosidation protocol introduced by Vorbrüggen and co-workers. Key interactions of the adenine moiety with COMT were measured with a radiochemical assay. Several bisubstrate inhibitors, most notably the adenine replacements thiopyridine, purine, N-methyladenine, and 6-methylpurine, displayed nanomolar $IC_{50}$ values (median inhibitory concentration) for COMT down to 6 nM. A series of six cocrystal structures of the bisubstrate inhibitors in ternary complexes with COMT and $Mg^{2+}$ confirm our predicted binding mode of the adenine replacements. The cocrystal structure of an inhibitor bearing no nucleobase can be regarded as an intermediate along the reaction coordinate of bisubstrate inhibitor binding to COMT. Our studies show that solvation varies with the type of adenine replacement, whereas among the adenine derivatives, the nitrogen atom at position 1 is essential for high affinity, while the exocyclic amino group is most efficiently substituted by a methyl group.
ISSN	09476539
e-ISSN	15213765
Journal	Chemistry - A European Journal
Issue Number	23
Volume Number	17
Language	English
Publisher	Wiley-VCH;ChemPubSoc Europe
Publisher Date	2011-05-27
Publisher Place	Germany
Access Restriction	Open
Subject Keyword	Adenine Chemistry Catechol O-Methyltransferase Inhibitors Catechol O-Methyltransferase Enzyme Inhibitors Chemical Synthesis Parkinson Disease Drug Therapy Catalysis Catalytic Domain Metabolism Crystallography, X-Ray Hydrogen Bonding Inhibitory Concentration 50 Kinetics Models, Molecular Molecular Structure Protein Binding Research Support, Non-U.S. Gov't
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Catalysis

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