3DZ4

Human AdoMetDC with 5'-[(2-carboxamidoethyl)methylamino]-5'-deoxy-8-methyladenosine

Summary for 3DZ4

• Entry DOI: 10.2210/pdb3dz4/pdb
• Related: 1I72 1I79 1I7B 1I7C 1I7M 1JEN 3DZ2 3DZ3 3DZ5 3DZ6 3DZ7
• Descriptor: S-adenosylmethionine decarboxylase beta chain, S-adenosylmethionine decarboxylase alpha chain, 1,4-DIAMINOBUTANE, ... (5 entities in total)
• Functional Keywords: complexes of adometdc with 8-substituted ligands, decarboxylase, lyase, pyruvate, s-adenosyl-l-methionine, spermidine biosynthesis, zymogen
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 38834.10

Authors

Bale, S.,McCloskey, D.E.,Pegg, A.E.,Secrist III, J.A.,Guida, W.C.,Ealick, S.E. (deposition date: 2008-07-29, release date: 2009-03-10, Last modification date: 2024-10-30)

Primary citation

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.
New Insights into the Design of Inhibitors of Human S-Adenosylmethionine Decarboxylase: Studies of Adenine C8 Substitution in Structural Analogues of S-Adenosylmethionine
J.Med.Chem., 52:1388-1407, 2009

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.

PubMed: 19209891
DOI: 10.1021/jm801126a

Experimental method

X-RAY DIFFRACTION (1.84 Å)