ALMASSY R, APPELT K, CHEN S, FEHER V, MARGOSIAK S, PINKO C, ZAIDI S, LEE JE, SMITH G, HORVATIN C, HOWELL P; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. F-741.

Quorex Pharmaceuticals, Carlsbad, CA.

BACKGROUND:: 5'-methylthioadenosine/S-adenosylhomocysteine (MTA/AdoHcy) nucleosidase catalyzes the cleavage of the glycosidic bond in MTA and AdoHcy. This enzyme is absent in mammalian cells. However, its activity is important for a variety of prokaryotic cellular processes, making it an attractive target for antibacterial drug design. METHODS: Enzymes from Staphylococcus aureus, Streptococcus pneumoniae and Haemophilus influenzae were cloned, purified, crystallized and their structures determined in the presence of either adenine, 8-amino adenine or formycin to better than 1.9A resolution. These structures are compared to the previously determined E. coli structures (Lee et al., Structure (2001) 9(10), 941-953) and amino acid sequences from other pathogenic species. RESULTS: The E. coli, S. aureus, S. pneumoniae and H. influenzae MTA/AdoHcy nucleosidase structures all show high sequence and tertiary structure conservation, particularly in the active site. This conservation suggests it is possible to design inhibitors to these enzymes that will be active against a variety of pathogenic enzymes and produce a broad-spectrum antibacterial drug. The structures of S. aureus bound to 8-amino adenine or formycin A as well as the structure of H. influenzae bound to adenine were all found in a closed conformation, similar to that seen in the E. coli complex with formycin A. The ligands are deeply buried within the enzyme's active site. Important enzyme-ligand interactions are identified in the adenine-binding site. Several structurally conserved water molecules are observed in the ribose-binding pocket. CONCLUSIONS: Structural information from a number of conserved MTA/AdoHcy nucleosidases can be useful in structure-based drug design of a broad-spectrum antibacterial drug.

Publication Types:

• Meeting Abstracts

Keywords:

• Adenine
• Base Sequence
• Binding Sites
• Catalysis
• Drug Design
• Formycins
• Haemophilus influenzae
• N-Glycosyl Hydrolases
• Ribose
• adenosylhomocysteine nucleosidase
• formycin
• genetics

Other ID:

• GWAIDS0028287

UI: 102267911

From Meeting Abstracts