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.
journal_name
Biochemistryjournal_title
Biochemistryauthors
Bale S,Brooks W,Hanes JW,Mahesan AM,Guida WC,Ealick SEdoi
10.1021/bi900590msubject
Has Abstractpub_date
2009-07-14 00:00:00pages
6423-30issue
27eissn
0006-2960issn
1520-4995journal_volume
48pub_type
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