Structure ofStaphylococcus aureus5′-methylthioadenosine/S-adenosylhomocysteine nucleosidase

Abstract

PDB Reference: 5 0 -methylthioadenosine/ S-adenosylhomocysteine nucleosidase, 3bl6, r3bl6sf.5 0 -Methylthioadenosine/S-adenosylhomocysteine nucleosidase (MTAN) catalyzes the irreversible cleavage of the glycosidic bond in 5 0 -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 (SaMTAN) 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 SaMTAN-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 0 atom of formycin A in the active site of SaMTAN, produces electron withdrawal from the ribosyl group and may explain the lower catalytic efficiency that SaMTAN exhibits when metabolizing MTA and SAH relative to the E. coli enzyme. The implications of this structure for broad-based antibiotic design are discussed.

Exploiting Quorum Sensing To Confuse Bacterial Pathogens

“…Studies utilizing kinetic isotope effects (KIEs) and crystal structures of MTANs in complex with known transition state analogues have allowed for transition state modeling of MTANs from E. coli, S. pneumoniae, Neisseria meningitidis, S. aureus, and V. cholerae and the subsequent design of analogue inhibitors (120)(121)(122)(149)(150)(151)(152)(153). Thus far, it appears that most MTANs share a fully dissociated S N 1 transition state characterized by a ribooxacarbenium ion (121,122,149,152), with the exception of MTANs from (149).…”

Structural and Biochemical Characterization of Chlamydia trachomatis Hypothetical Protein CT263 Supports That Menaquinone Synthesis Occurs through the Futalosine Pathway

“…Structural Comparison with SeMTAN Reveals That CT263 Is in the Closed Form-MTANs have been extensively studied from a structure/function standpoint in a variety of medically relevant pathogens, including E. coli (41,56,58), H. pylori (52,53,57,59), S. aureus (60), and S. enterica (54), among others. All of these structures have crystallized with a conserved dimer interface (Fig.…”

Mechanism of substrate specificity in 5′-methylthioadenosine/S-adenosylhomocysteine nucleosidases

“…In monomers B and D, Glu202 assumes a single conformation not previously observed in any of the available MTAN structures (Singh et al, 2006; Siu et al, 2008a,b; Park et al, 2009, 2006; Lee et al, 2001, 2003, 2005). In monomers A and C, an additional conformation is observed at 40% occupancy (Fig.…”