Abstract
The universality of peptidoglycan in bacteria underlies the broad spectrum of many successful antibiotics. However, in our times of widespread resistance, the diversity of peptidoglycan modifications offers a variety of new antibacterials targets. In some Gram-positive species such as Streptococcus pneumoniae, Staphylococcus aureus, or Mycobacterium tuberculosis, the second residue of the peptidoglycan precursor, D-glutamate, is amidated into iso-D-glutamine by the essential amidotransferase MurT/GatD complex. Here, we present the structure of this complex at 3.0 Å resolution. MurT has central and C-terminal domains similar to Mur ligases with a cysteine-rich insertion, which probably binds zinc, contributing to the interface with GatD. The mechanism of amidation by MurT is likely similar to the condensation catalyzed by Mur ligases. GatD is a glutaminase providing ammonia that is likely channeled to the MurT active site through a cavity network. The structure and assay presented here constitute a knowledge base for future drug development studies.
Highlights
The universality of peptidoglycan in bacteria underlies the broad spectrum of many successful antibiotics
penicillinbinding proteins (PBPs) are responsible in some Corynebacteria for the 2–4 linkage with an intermediate diamino acid
We present the structure of a MurT/GatD complex, from the human pathogen S. pneumoniae
Summary
The universality of peptidoglycan in bacteria underlies the broad spectrum of many successful antibiotics. In some Gram-positive species such as Streptococcus pneumoniae, Staphylococcus aureus, or Mycobacterium tuberculosis, the second residue of the peptidoglycan precursor, D-glutamate, is amidated into iso-Dglutamine by the essential amidotransferase MurT/GatD complex. The peptide component shows even greater variety arising from the diverse residues assembled into the precursor pentapeptide by the Mur ligases C, D, E, and F1. The first residue is generally an L-Ala, but can be Gly or L-Ser. The second amino acid is D-Glu. The third residue attached to the C5 of the D-Glu can be L-Lys, as in Streptococcus pneumoniae, or a meso-diaminopimelate, as in many Gram-negative species, or a variety of other residues. L,D-transpeptidases can form 3–3 linkages in many species, and account for most of the cross-linking in Mycobacteria, Clostridia, and in some β-lactam-resistant bacteria. The degree of cross-linking and trimming is variable[1]
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