1106913-36-3Relevant academic research and scientific papers
New insights into the design of inhibitors of human S-adenosylmethionine decarboxylase: studies of adenine C8 substitution in structural analogues of S-adenosylmethionine
McCloskey, Diane E.,Bale, Shridhar,Secrist III, John A.,Tiwari, Anita,Moss III, Thomas H.,Valiyaveettil, Jacob,Brooks, Wesley H.,Guida, Wayne C.,Pegg, Anthony E.,Ealick, Steven E.
experimental part, p. 1388 - 1407 (2009/12/07)
S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical enzyme in the polyamine biosynthetic pathway and depends on a pyruvoyl group for the decarboxylation process. The crystal structures of the enzyme with various inhibitors at the active site have shown that the adenine base of the ligands adopts an unusual syn conformation when bound to the enzyme. To determine whether compounds that favor the syn conformation in solution would be more potent AdoMetDC inhibitors, several series of AdoMet substrate analogues with a variety of substituents at the 8-position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. The biochemical analysis indicated that an 8-methyl substituent resulted in more potent inhibitors, yet most other 8-substitutions provided no benefit over the parent compound. To understand these results, we used computational modeling and X-ray crystallography to study C8-substituted adenine analogues bound in the active site.
5'-SUBSTITUTED ADENOSYNES, PREPARATION THEREOF AND USE AS INHIBITORS OF S-ADENOSYLMETHIONINE DECARBOXYLASE
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Page/Page column 14, (2009/03/07)
The crystal structure of the complex of S-adenosylmethionine methyl ester with hΛdoMetDC F223A, a mutant where the stacking of the aromatic rings of F7, adenine and F223 would be eliminated. The structure of this mutant with the ester shows that the ligand still maintains a syn conformation aided by pi-pi interactions to F7, hydrogen bonds to the backbone of Glu67, and electrostatic interactions. Several series of AdoMet substrate analogues with a variety of substituents at the 8 position of adenine were synthesized and analyzed for their ability to inhibit hAdoMetDC. To understand these results, virtual modeling of the enzyme inhibitor complexes and the crystal structures of human AdoMetDC with 5'-deoxy-5'-[N-methyl-N-[2- (aminooxy)ethyl]amino-8-rnethyl]adenosine (MAOEMA) and 5'-deoxy-5'-[N-methyl-N-[4- (aminooxy)butyl]amino-8-ethyl]adenosine (MAOBEA) at the active site have been determined experimentally.
