Multimodular penicillin binding proteins: An enigmatic family of orthologsand paralogs

The monofunctional penicillin-binding oo-peptidases and penicillin-hydrolyz ing serine beta-lactamases diverged from a common ancestor by the acquisiti on of structural changes in the polypeptide chain while retaining the same folding three-motif amino acid sequence signature, serine-assisted catalyti c mechanism, and active-site topology. Fusion events gave rise to multimodu lar penicillin-binding proteins (PBPs). The acyl serine transferase penicil lin-binding (PB) module possesses the three active-site defining motifs of the superfamily; it is linked to the carboxy end of a non-penicillin-bindin g (n-PB) module through a conserved fusion site; the two modules form a sin gle polypeptide chain which folds on the exterior of the plasma membrane an d is anchored by a transmembrane spanner; and the full-size PBPs cluster in to two classes, A and B. In the class A PBPs, the n-PB modules are a contin uum of diverging sequences; they possess a five-motif amino acid sequence s ignature, and conserved dicarboxylic amino acid residues are probably eleme nts of the glycosyl transferase catalytic center. The PB modules fall into five subclasses: A1 and A2 in gram-negative bacteria and A3, A4 and A5 in g ram-positive bacteria. The foil-size class A PBPs combine the required enzy matic activities for peptidoglycan assembly from lipid-transported disaccha ride-peptide units and almost certainly prescribe different, PB-module spec ific traits in peptidoglycan cross-linking. In the class B PBPs, the PB and n-PB modules cluster in a concerted manner: A PB module of subclass B2 or B3 is linked to an n-PB module of subclass B2 or B3 gram-negative bacteria, and a PB module of subclass B1, B4, or B5 is linked to an n-PB module of s ubclass B1, B4, or B5 in gram-positive bacteria. Class B PBPs are involved in cell morphogenesis. The three motifs borne by the n-PB modules are proba bly sites for module-module interaction and the polypeptide stretches which extend between motifs 1 and 2 are sites for protein-protein interaction. T he full-size class B PBPs are an assortment of orthologs and paralogs, whic h prescribe traits as complex as wall expansion and septum formation. PBPs of subclass B1 are unique to gram-positive bacteria. They are not essential brit they represent an important mechanism of resistance to penicillin amo ng the enterococci and staphylococci. Natural evolution and PBP- and beta-l actamase-mediated resistance show that the ability of the catalytic centers to adapt their. properties to new situations is limitless. Studies of the reaction pathways by rising the methods of quantum chemistry suggest that r esistance to penicillin is a road of no return.