Figure 1.

The PG biosynthesis pathway

(1) The cytoplasmic stage is characterized by the formation of UDP-MurNAc-pentapeptide (UDP-MurNAc-5P) by MurA-MurF. The pentapeptide stem peptide usually comprises L-Ala-γ-D-Glu-L-Lys-D-Ala-D-Ala in most Gram-positive organisms including the pneumococcus.

(2) At the internal face of the cytoplasmic membrane, MraY catalyzes the formation of Lipid I from UDP-MurNAc-5P to undecaprenyl-pyrophosphate, which is then converted to Lipid II by MurG. In S. pneumoniae, the second position D-glutamyl α-carboxyl is amidated to D-iso-glutamine (iGln) by the MurT/GatD complex, and in some cases a dipeptide branch of either L-Ser/L-Ala or L-Ala/L-Ala may be appended at the ε-amino group of the third-position lysine by MurM and MurN, respectively. The exact order of the cytoplasmic membrane steps remains uncertain, but here for clarity they appear as a linear sequence, with conversion to Lipid II occurring before peptide stem modifications, and amidation occurring before branching. Lipid II is translocated across the membrane by MurJ.

(3) At the external face of the cytoplasmic membrane, class A PBPs and complexes of SEDs-Class B PBPs form glycan chains by transglycosylation (TG), with the concomitant release of undecaprenyl-pyrophosphate, and form either direct or indirect crosslinks throughout the PG layer via transpeptidation (TP). Nucleotide sugars UDP-GlcNAc and UDP-MurNAc and the sugars GlcNAc and MurNAc are signified by blue, violet, dark-blue, and purple elongated hexagons, respectively. Figure created using BioRender.com.