3H0W

Human AdoMetDC with 5'-Deoxy-5'-[(N-dimethyl)amino]-8-methyl-adenosine

Summary for 3H0W

• Entry DOI: 10.2210/pdb3h0w/pdb
• Related: 1I72 1I79 1I7B 1I7C 1I7M 1JEN 3H0V
• Descriptor: S-adenosylmethionine decarboxylase proenzyme, 1,4-DIAMINOBUTANE, 5'-deoxy-5'-(dimethylamino)-8-methyladenosine, ... (6 entities in total)
• Functional Keywords: adometdc with competitive substrate analogs, autocatalytic cleavage, decarboxylase, lyase, phosphoprotein, polyamine biosynthesis, pyruvate, s-adenosyl-l-methionine, schiff base, spermidine biosynthesis, zymogen
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 38795.07

Authors

Bale, S.,Brooks, W.H.,Hanes, J.W.,Mahesan, A.M.,Guida, W.C.,Ealick, S.E. (deposition date: 2009-04-10, release date: 2009-06-30, Last modification date: 2023-11-15)

Primary citation

Bale, S.,Brooks, W.,Hanes, J.W.,Mahesan, A.M.,Guida, W.C.,Ealick, S.E.
Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.
Biochemistry, 48:6423-6430, 2009

PubMed Abstract: S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway. Inhibition of this pathway and subsequent depletion of polyamine levels is a viable strategy for cancer chemotherapy and for the treatment of parasitic diseases. Substrate analogue inhibitors display an absolute requirement for a positive charge at the position equivalent to the sulfonium of S-adenosylmethionine. We investigated the ligand specificity of AdoMetDC through crystallography, quantum chemical calculations, and stopped-flow experiments. We determined crystal structures of the enzyme cocrystallized with 5'-deoxy-5'-dimethylthioadenosine and 5'-deoxy-5'-(N-dimethyl)amino-8-methyladenosine. The crystal structures revealed a favorable cation-pi interaction between the ligand and the aromatic side chains of Phe7 and Phe223. The estimated stabilization from this interaction is 4.5 kcal/mol as determined by quantum chemical calculations. Stopped-flow kinetic experiments showed that the rate of the substrate binding to the enzyme greatly depends on Phe7 and Phe223, thus supporting the importance of the cation-pi interaction.

PubMed: 19527050
DOI: 10.1021/bi900590m

Experimental method

X-RAY DIFFRACTION (1.81 Å)