Download MendeleyNew Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine
McCloskey, D.E., Bale, S., Secrist III, J.A., Tiwari, A., Moss III, T.H., Valiyaveettil, J., Brooks, W.H., Guida, W.C., Pegg, A.E., Ealick, S.E.(2009) J Med Chem 52: 1388-1407
- PubMed: 19209891
- DOI: https://doi.org/10.1021/jm801126a
- Primary Citation of Related Structures:
3DZ2, 3DZ3, 3DZ4, 3DZ5, 3DZ6, 3DZ7 - PubMed Abstract:
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 C(8)-substituted adenine analogues bound in the active site.
Organizational Affiliation:
Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
