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Orthologous and Paralogous AmpD Peptidoglycan Amidases from Gram-Negative Bacteria

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ABSTRACT

Cell wall recycling and β-lactam antibiotic resistance are linked in Enterobacteriaceae and in Pseudomonas aeruginosa. This process involves a large number of murolytic enzymes, among them a cytoplasmic peptidoglycan amidase AmpD, which plays an essential role by cleaving the peptide stem from key intermediates en route to the β-lactamase production (a resistance mechanism) and cell wall recycling. Uniquely, P. aeruginosa has two additional paralogues of AmpD, designated AmpDh2 and AmpDh3, which are periplasmic enzymes. Despite the fact that AmpDh2 and AmpDh3 share a common motif for their respective catalytic domains, they are each comprised of multidomain architectures and exhibit distinct oligomerization properties. We review herein the structural and biochemical properties of orthologous and paralogous AmpD proteins and discuss their implication in cell wall recycling and antibiotic resistance processes.

No MeSH data available.


General cell wall recycling mechanism in Gram-negative bacteria. Figure adapted from Ref.14Yellow bond indicates where AmpD, AmpDh2, and AmpDh3 cleave. Red and blue lines indicate bonds cleaved by LTs and NagZ, respectively.
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f1: General cell wall recycling mechanism in Gram-negative bacteria. Figure adapted from Ref.14Yellow bond indicates where AmpD, AmpDh2, and AmpDh3 cleave. Red and blue lines indicate bonds cleaved by LTs and NagZ, respectively.

Mentions: Bacterial cell wall recycling is set in motion by degradation of PG, the major constituent of the cell wall, by the action of lytic transglycosylases4–6 (Fig. 1). These enzymes digest the peptidoglycan saccharide backbone to generate various fragmentation products, referred to as muropeptides.7 The major end product is N-acetyl-β-d-glucosamine-(1–4)-1,6-anhydro-N-acetyl-β-d-muramyl-peptide (NAG-anhNAM-peptide, 1 in Fig. 2), which is internalized to the cytoplasm by the permease AmpG. As studied in the system in Citrobacter freundii, once in the cytoplasm, the disaccharide is hydrolyzed by glucosaminidase NagZ to result in 1,6-anhydro-N-acetyl-β-d-muramyl-peptide (anhNAM-peptide, 2 in Fig. 2) and N-acetylglucosamine, which then serves as the substrate for the protease AmpD. Thus, AmpD peptidoglycan amidase removes the peptide stem from anhydro-N-acetyl-β-d-muramyl-peptide (2) at the amide bond of the lactyl moiety8 (Fig. 1). AmpD exhibits high selectivity for anhydromuramyl peptides and this selectivity ensures that AmpD participates in muropeptide recycling without degrading other potential peptide substrates. This reaction takes place in the bacterial cytoplasm and its substrate is believed to be an important player both in the peptidoglycan recycling events and in an induction process that leads to the expression of β-lactamase, a key β-lactam antibiotic resistance enzyme (Fig. 1). Removal of the peptide from the substrate for AmpD (Fig. 1) is at the crossroads of the induction of the AmpC β-lactamase and commitment to recycling of the cell wall.2,5,9 That is to say that the AmpD reaction shuts down the mechanism for the induction of β-lactamase production and directs the process to recycling.


Orthologous and Paralogous AmpD Peptidoglycan Amidases from Gram-Negative Bacteria
General cell wall recycling mechanism in Gram-negative bacteria. Figure adapted from Ref.14Yellow bond indicates where AmpD, AmpDh2, and AmpDh3 cleave. Red and blue lines indicate bonds cleaved by LTs and NagZ, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036320&req=5

f1: General cell wall recycling mechanism in Gram-negative bacteria. Figure adapted from Ref.14Yellow bond indicates where AmpD, AmpDh2, and AmpDh3 cleave. Red and blue lines indicate bonds cleaved by LTs and NagZ, respectively.
Mentions: Bacterial cell wall recycling is set in motion by degradation of PG, the major constituent of the cell wall, by the action of lytic transglycosylases4–6 (Fig. 1). These enzymes digest the peptidoglycan saccharide backbone to generate various fragmentation products, referred to as muropeptides.7 The major end product is N-acetyl-β-d-glucosamine-(1–4)-1,6-anhydro-N-acetyl-β-d-muramyl-peptide (NAG-anhNAM-peptide, 1 in Fig. 2), which is internalized to the cytoplasm by the permease AmpG. As studied in the system in Citrobacter freundii, once in the cytoplasm, the disaccharide is hydrolyzed by glucosaminidase NagZ to result in 1,6-anhydro-N-acetyl-β-d-muramyl-peptide (anhNAM-peptide, 2 in Fig. 2) and N-acetylglucosamine, which then serves as the substrate for the protease AmpD. Thus, AmpD peptidoglycan amidase removes the peptide stem from anhydro-N-acetyl-β-d-muramyl-peptide (2) at the amide bond of the lactyl moiety8 (Fig. 1). AmpD exhibits high selectivity for anhydromuramyl peptides and this selectivity ensures that AmpD participates in muropeptide recycling without degrading other potential peptide substrates. This reaction takes place in the bacterial cytoplasm and its substrate is believed to be an important player both in the peptidoglycan recycling events and in an induction process that leads to the expression of β-lactamase, a key β-lactam antibiotic resistance enzyme (Fig. 1). Removal of the peptide from the substrate for AmpD (Fig. 1) is at the crossroads of the induction of the AmpC β-lactamase and commitment to recycling of the cell wall.2,5,9 That is to say that the AmpD reaction shuts down the mechanism for the induction of β-lactamase production and directs the process to recycling.

View Article: PubMed Central - PubMed

ABSTRACT

Cell wall recycling and β-lactam antibiotic resistance are linked in Enterobacteriaceae and in Pseudomonas aeruginosa. This process involves a large number of murolytic enzymes, among them a cytoplasmic peptidoglycan amidase AmpD, which plays an essential role by cleaving the peptide stem from key intermediates en route to the β-lactamase production (a resistance mechanism) and cell wall recycling. Uniquely, P. aeruginosa has two additional paralogues of AmpD, designated AmpDh2 and AmpDh3, which are periplasmic enzymes. Despite the fact that AmpDh2 and AmpDh3 share a common motif for their respective catalytic domains, they are each comprised of multidomain architectures and exhibit distinct oligomerization properties. We review herein the structural and biochemical properties of orthologous and paralogous AmpD proteins and discuss their implication in cell wall recycling and antibiotic resistance processes.

No MeSH data available.