Open AccessStructure of Staphylococcus aureus 5′‐methylthioadenosine/ S ‐adenosylhomocysteine nucleosidase
Author(s) -
Siu Karen K. W.,
Lee Jeffrey E.,
Smith G. David,
HorvatinMrakovcic Cathy,
Howell P. Lynne
Publication year - 2008
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
ISSN - 1744-3091
DOI - 10.1107/s1744309108009275
Subject(s) - staphylococcus aureus , chemistry , microbiology and biotechnology , biology , genetics , bacteria
5′‐Methylthioadenosine/ S ‐adenosylhomocysteine nucleosidase (MTAN) catalyzes the irreversible cleavage of the glycosidic bond in 5′‐methylthioadenosine (MTA) and S ‐adenosylhomocysteine (SAH) and plays a key role in four metabolic processes: biological methylation, polyamine biosynthesis, methionine recycling and bacterial quorum sensing. The absence of the nucleosidase in mammalian species has implicated this enzyme as a target for antimicrobial drug design. MTAN from the pathogenic bacterium Staphylococcus aureus ( Sa MTAN) has been kinetically characterized and its structure has been determined in complex with the transition‐state analogue formycin A (FMA) at 1.7 Å resolution. A comparison of the Sa MTAN–FMA complex with available Escherichia coli MTAN structures shows strong conservation of the overall structure and in particular of the active site. The presence of an extra water molecule, which forms a hydrogen bond to the O4′ atom of formycin A in the active site of Sa MTAN, produces electron withdrawal from the ribosyl group and may explain the lower catalytic efficiency that Sa MTAN exhibits when metabolizing MTA and SAH relative to the E. coli enzyme. The implications of this structure for broad‐based antibiotic design are discussed.