The crystal structure of human S-adenosylmethionine decarboxylase at 2.25 Å resolution reveals a novel fold

Jennifer L. Ekstrom, I. Irimpan Mathews, Bruce Stanley, Anthony Pegg, Steven E. Ealick

68 Scopus citations

Abstract

Background: S-Adenosylmethionine decarboxylase (AdoMetDC) is a critical regulatory enzyme of the polyamine synthetic pathway, and a well-studied drug target. The AdoMetDC decarboxylation reaction depends upon a pyruvoyl cofactor generated via an intramolecular proenzyme self-cleavage reaction. Both the proenzyme-processing and substrate-decarboxylation reactions are allosterically enhanced by putrescine. Structural elucidation of this enzyme is necessary to fully interpret the existing mutational and inhibitor- binding data, and to suggest further experimental studies. Results: The structure of human AdoMetDC has been determined to 2.25 Å resolution using multiwavelength anomalous diffraction (MAD) phasing methods based on 22 selenium-atom positions. The quaternary structure of the mature AdoMetDC is an (αβ)2 dimer, where α and β represent the products of the proenzyme self-cleavage reaction. The architecture of each (αβ) monomer is a novel four-layer α/β-sandwich fold, comprised of two antiparallel eight-stranded β sheets flanked by several α and 310 helices. Conclusions: The structure and topology of AdoMetDC display internal symmetry, suggesting that this protein may be the product of an ancient gene duplication. The positions of conserved, functionally important residues suggest the location of the active site and a possible binding site for the effector molecule putrescine.

Original languageEnglish (US)
Pages (from-to)583-595
Number of pages13
JournalStructure
Volume7
Issue number5
DOIs
Publication statusPublished - May 1999

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