5ENZ

S. aureus MnaA-UDP co-structure

5ENZ の概要

• エントリーDOI: 10.2210/pdb5enz/pdb
• 分子名称: UDP-GlcNAc 2-epimerase, URIDINE-5'-DIPHOSPHATE, SULFATE ION, ... (6 entities in total)
• 機能のキーワード: sugar-nucleotide epimerase, rossmann fold, two domains, glycogen phosphorylase superfamily, udp, dimer, isomerase
• 由来する生物種: Staphylococcus aureus
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 89008.87

構造登録者

Fischmann, T.O. (登録日: 2015-11-09, 公開日: 2016-04-27, 最終更新日: 2023-09-27)

主引用文献

Mann, P.A.,Muller, A.,Wolff, K.A.,Fischmann, T.,Wang, H.,Reed, P.,Hou, Y.,Li, W.,Muller, C.E.,Xiao, J.,Murgolo, N.,Sher, X.,Mayhood, T.,Sheth, P.R.,Mirza, A.,Labroli, M.,Xiao, L.,McCoy, M.,Gill, C.J.,Pinho, M.G.,Schneider, T.,Roemer, T.
Chemical Genetic Analysis and Functional Characterization of Staphylococcal Wall Teichoic Acid 2-Epimerases Reveals Unconventional Antibiotic Drug Targets.
Plos Pathog., 12:e1005585-e1005585, 2016

PubMed Abstract: Here we describe a chemical biology strategy performed in Staphylococcus aureus and Staphylococcus epidermidis to identify MnaA, a 2-epimerase that we demonstrate interconverts UDP-GlcNAc and UDP-ManNAc to modulate substrate levels of TarO and TarA wall teichoic acid (WTA) biosynthesis enzymes. Genetic inactivation of mnaA results in complete loss of WTA and dramatic in vitro β-lactam hypersensitivity in methicillin-resistant S. aureus (MRSA) and S. epidermidis (MRSE). Likewise, the β-lactam antibiotic imipenem exhibits restored bactericidal activity against mnaA mutants in vitro and concomitant efficacy against 2-epimerase defective strains in a mouse thigh model of MRSA and MRSE infection. Interestingly, whereas MnaA serves as the sole 2-epimerase required for WTA biosynthesis in S. epidermidis, MnaA and Cap5P provide compensatory WTA functional roles in S. aureus. We also demonstrate that MnaA and other enzymes of WTA biosynthesis are required for biofilm formation in MRSA and MRSE. We further determine the 1.9Å crystal structure of S. aureus MnaA and identify critical residues for enzymatic dimerization, stability, and substrate binding. Finally, the natural product antibiotic tunicamycin is shown to physically bind MnaA and Cap5P and inhibit 2-epimerase activity, demonstrating that it inhibits a previously unanticipated step in WTA biosynthesis. In summary, MnaA serves as a new Staphylococcal antibiotic target with cognate inhibitors predicted to possess dual therapeutic benefit: as combination agents to restore β-lactam efficacy against MRSA and MRSE and as non-bioactive prophylactic agents to prevent Staphylococcal biofilm formation.

PubMed: 27144276
DOI: 10.1371/journal.ppat.1005585

実験手法

X-RAY DIFFRACTION (1.91 Å)