Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.

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

Biochemistry

journal_title

Biochemistry

authors

Bale S,Brooks W,Hanes JW,Mahesan AM,Guida WC,Ealick SE

doi

10.1021/bi900590m

subject

Has Abstract

pub_date

2009-07-14 00:00:00

pages

6423-30

issue

27

eissn

0006-2960

issn

1520-4995

journal_volume

48

pub_type

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