Bacterial AmpD at the crossroads of peptidoglycan recycling and manifestation of antibiotic resistance.
The bacterial enzyme AmpD is an early catalyst in commitment of cell wall metabolites to the recycling events within the cytoplasm. The key internalized metabolite of cell wall recycling, beta-D-N-acetylglucosamine-(1-->4)-1,6-anhydro-beta-N-acetylmuramyl-L-Ala-gamma-D-Glu-meso-DAP-D-Ala-D-Ala (compound 1), is a poor substrate for AmpD. Two additional metabolites, 1,6-anhydro-N-acetylmuramyl-peptidyl derivatives 2a and 2c, served as substrates for AmpD with a k(cat)/K(m) of >10(4) M(-1) s(-1). The enzyme hydrolytically processes the lactyl amide bond of the 1,6-anhydro-N-acetylmuramyl moiety. The syntheses of these substrates and other ligands are reported herein, which made the characterization of the enzymic reaction possible. Furthermore, it is documented that the enzyme is specific for both the atypical peptide stem of the cell wall fragments and the presence of the sterically encumbered 1,6-anhydro-N-acetylmuramyl moiety; hence it is a peptidase with a unique function in bacterial physiology. The implications of the function of this catalyst for the entry into the cell wall recycling events and the reversal of induction of the production of beta-lactamase, an antibiotic resistance determinant, are discussed.
Lee
Mijoon
M
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, USA.
Zhang
Weilie
W
Hesek
Dusan
D
Noll
Bruce C
BC
Boggess
Bill
B
Mobashery
Shahriar
S
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016971:Citrobacter freundii / Q000201:enzymology* / Q000235:genetics; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial; D004926:Escherichia coli / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D008958:Models, Molecular; D015394:Molecular Structure; D009238:N-Acetylmuramoyl-L-alanine Amidase / Q000235:genetics / Q000378:metabolism*; D010457:Peptidoglycan / Q000737:chemistry* / Q000378:metabolism*; D013379:Substrate Specificity; D001618:beta-Lactamases / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D010457:Peptidoglycan; C062460:AmpD protein, Bacteria; D009238:N-Acetylmuramoyl-L-alanine Amidase; D001618:beta-Lactamases