Structural aspects for evolution β-lactamases from penicillin-binding proteins

Samy Meroueh, George Minasov, Wenlin Lee, Brian K. Shoichet, Shahriar Mobashery

Research output: Contribution to journalArticle

53 Citations (Scopus)

Abstract

Penicillin-binding proteins (PBPs), biosynthetic enzymes of bacterial cell wall assembly, and β-lactamases, resistance enzymes to β-lactam antibiotics, are related to each other from an evolutionary point of view. Massova and Mobashery (Antimicrob. Agents Chemother. 1998, 42, 1-17) have proposed that for β-lactamases to have become effective at their function as antibiotic resistance enzymes, they would have had to undergo structure alterations such that they would not interact with the peptidoglycan, which is the substrate for PBPs. A cephalosporin analogue, 7β-[N-Acetyl-L-alanyl-γ-D-glutamyl-L-lysine] -3-acetoxymethyl-3-cephem-carboxylic acid (compound 6), was conceived and synthesized to test this notion. The X-ray structure of the complex of this cephalosporin bound to the active site of the deacylation-deficient Q120L/Y150E variant of the class C AmpC β-lactamase from Escherichia coli was solved at 1.71 Å resolution. This complex revealed that the surface for interaction with the strand of peptidoglycan that acylates the active site, which is present in PBPs, is absent in the β-lactamase active site. Furthermore, insertion of a peptide in the β-lactamase active site at a location where the second strand of peptidoglycan in some PBPs binds has effectively abolished the possibility for such interaction with the β-lactamase. A 2.6 ns dynamics simulation was carried out for the complex, which revealed that the peptidoglycan surrogate (i.e., the active-site-bound ligand) undergoes substantial motion and is not stabilized for binding within the active site. These factors taken together disclose the set of structure modifications in the antibiotic resistance enzyme that prevent it from interacting with the peptidoglycan, en route to achieving catalytic proficiency for their intended function.

Original languageEnglish (US)
Pages (from-to)9612-9618
Number of pages7
JournalJournal of the American Chemical Society
Volume125
Issue number32
DOIs
StatePublished - Aug 13 2003
Externally publishedYes

Fingerprint

Penicillin-Binding Proteins
Peptidoglycan
Catalytic Domain
Antibiotics
Enzymes
Cephalosporins
Anti-Bacterial Agents
Microbial Drug Resistance
Lactams
Carboxylic acids
Escherichia coli
Peptides
Carboxylic Acids
Ligands
Cells
Lysine
X rays
Cell Wall
Carrier Proteins
Computer simulation

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Structural aspects for evolution β-lactamases from penicillin-binding proteins. / Meroueh, Samy; Minasov, George; Lee, Wenlin; Shoichet, Brian K.; Mobashery, Shahriar.

In: Journal of the American Chemical Society, Vol. 125, No. 32, 13.08.2003, p. 9612-9618.

Research output: Contribution to journalArticle

Meroueh, Samy ; Minasov, George ; Lee, Wenlin ; Shoichet, Brian K. ; Mobashery, Shahriar. / Structural aspects for evolution β-lactamases from penicillin-binding proteins. In: Journal of the American Chemical Society. 2003 ; Vol. 125, No. 32. pp. 9612-9618.
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