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Emerging knowledge of regulatory roles of D-amino acids in bacteria.

Cava F, Lam H, de Pedro MA, Waldor MK - Cell. Mol. Life Sci. (2010)

Bottom Line: Many diverse bacterial phyla synthesize and release D-amino acids, including D-Met and D-Leu, which were not previously known to be made.These noncanonical D-amino acids regulate cell wall remodeling in stationary phase and cause biofilm dispersal in aging bacterial communities.Elucidating the mechanisms by which D-amino acids govern cell wall remodeling and biofilm disassembly will undoubtedly reveal new paradigms for understanding how extracytoplasmic processes are regulated as well as lead to development of novel therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, and Howard Hughes Medical Institute, Boston, MA 02115, USA. fcava@rics.bwh.harvard.edu

ABSTRACT
The D-enantiomers of amino acids have been thought to have relatively minor functions in biological processes. While L-amino acids clearly predominate in nature, D-amino acids are sometimes found in proteins that are not synthesized by ribosomes, and D-Ala and D-Glu are routinely found in the peptidoglycan cell wall of bacteria. Here, we review recent findings showing that D-amino acids have previously unappreciated regulatory roles in the bacterial kingdom. Many diverse bacterial phyla synthesize and release D-amino acids, including D-Met and D-Leu, which were not previously known to be made. These noncanonical D-amino acids regulate cell wall remodeling in stationary phase and cause biofilm dispersal in aging bacterial communities. Elucidating the mechanisms by which D-amino acids govern cell wall remodeling and biofilm disassembly will undoubtedly reveal new paradigms for understanding how extracytoplasmic processes are regulated as well as lead to development of novel therapeutics.

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Related in: MedlinePlus

Model of PG remodeling governed by d-amino acid release in stationary phase. PG in V.cholerae is composed of linear glycan strands made up of repeating disaccharide units of GlcNAc and MurNAc cross-linked by short peptides that consist of l-Ala, d-Glu, meso-diaminopimelic acid (m-DAP), and d-Ala. In stationary phase, d-Met (bluecircles) and d-Leu (redcircles) are produced by BsrV, a periplasmic racemase. These d-amino acids (1) are incorporated at the 4th position of the PG-peptide bridge where d-Ala is usually found, (2) regulate the activity of periplasmic enzymes including penicillin-binding proteins (PBPs), which synthesize and modify PG, and (3) are released into the extracellular milieu where d-amino acids regulate the PG of other bacteria. OM Outer membrane, IM inner membrane
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Fig4: Model of PG remodeling governed by d-amino acid release in stationary phase. PG in V.cholerae is composed of linear glycan strands made up of repeating disaccharide units of GlcNAc and MurNAc cross-linked by short peptides that consist of l-Ala, d-Glu, meso-diaminopimelic acid (m-DAP), and d-Ala. In stationary phase, d-Met (bluecircles) and d-Leu (redcircles) are produced by BsrV, a periplasmic racemase. These d-amino acids (1) are incorporated at the 4th position of the PG-peptide bridge where d-Ala is usually found, (2) regulate the activity of periplasmic enzymes including penicillin-binding proteins (PBPs), which synthesize and modify PG, and (3) are released into the extracellular milieu where d-amino acids regulate the PG of other bacteria. OM Outer membrane, IM inner membrane

Mentions: Exactly how d-amino acid-dependent cell wall remodeling occurs remains to be determined. Incorporation of unusual d-amino acids (such as d-Met or d-Leu) into the PG polymer could modulate the strength and flexibility of this polymer (Fig. 4). Furthermore, PBPs and other enzymes that modify PG may have altered affinity for and activity on d-amino acid-modified muropeptides. However, it is unlikely that all of the differences in PG composition, structure, and amount observed between V. cholerae wild-type and bsrV mutant strains can be solely attributed to the incorporation of d-amino acids into PG. Supporting this idea, we found that 2.0 mM d-Ala stimulated the conversion of rod-shaped mrcA cells to spheres, even though d-Ala is already present at the site where d-Met or d-Leu is incorporated. Thus, d-Ala, and presumably other d-amino acids, have effects that are not merely consequences of their incorporation into PG. In this regard, d-amino acids likely regulate the periplasmic enzymes that synthesize and modify the PG polymer. We found that d- but not l-Met blocks the binding of a fluorescent derivative of penicillin G to several V. cholerae PBPs [77]. This result suggests that free amino acids accumulated in the periplasm might compete with muropeptide moieties for PBP active sites, thereby serving as regulators of PBP activity. While the exact identity of these PBPs remains to be determined, this observation suggests that d-amino acids may be direct modulators of PBP activity under stationary phase conditions. Further genetic and biochemical analyses of d-amino acid targets are necessary to define the mechanism(s) of d-amino acid action on cell wall PG.Fig. 4


Emerging knowledge of regulatory roles of D-amino acids in bacteria.

Cava F, Lam H, de Pedro MA, Waldor MK - Cell. Mol. Life Sci. (2010)

Model of PG remodeling governed by d-amino acid release in stationary phase. PG in V.cholerae is composed of linear glycan strands made up of repeating disaccharide units of GlcNAc and MurNAc cross-linked by short peptides that consist of l-Ala, d-Glu, meso-diaminopimelic acid (m-DAP), and d-Ala. In stationary phase, d-Met (bluecircles) and d-Leu (redcircles) are produced by BsrV, a periplasmic racemase. These d-amino acids (1) are incorporated at the 4th position of the PG-peptide bridge where d-Ala is usually found, (2) regulate the activity of periplasmic enzymes including penicillin-binding proteins (PBPs), which synthesize and modify PG, and (3) are released into the extracellular milieu where d-amino acids regulate the PG of other bacteria. OM Outer membrane, IM inner membrane
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3037491&req=5

Fig4: Model of PG remodeling governed by d-amino acid release in stationary phase. PG in V.cholerae is composed of linear glycan strands made up of repeating disaccharide units of GlcNAc and MurNAc cross-linked by short peptides that consist of l-Ala, d-Glu, meso-diaminopimelic acid (m-DAP), and d-Ala. In stationary phase, d-Met (bluecircles) and d-Leu (redcircles) are produced by BsrV, a periplasmic racemase. These d-amino acids (1) are incorporated at the 4th position of the PG-peptide bridge where d-Ala is usually found, (2) regulate the activity of periplasmic enzymes including penicillin-binding proteins (PBPs), which synthesize and modify PG, and (3) are released into the extracellular milieu where d-amino acids regulate the PG of other bacteria. OM Outer membrane, IM inner membrane
Mentions: Exactly how d-amino acid-dependent cell wall remodeling occurs remains to be determined. Incorporation of unusual d-amino acids (such as d-Met or d-Leu) into the PG polymer could modulate the strength and flexibility of this polymer (Fig. 4). Furthermore, PBPs and other enzymes that modify PG may have altered affinity for and activity on d-amino acid-modified muropeptides. However, it is unlikely that all of the differences in PG composition, structure, and amount observed between V. cholerae wild-type and bsrV mutant strains can be solely attributed to the incorporation of d-amino acids into PG. Supporting this idea, we found that 2.0 mM d-Ala stimulated the conversion of rod-shaped mrcA cells to spheres, even though d-Ala is already present at the site where d-Met or d-Leu is incorporated. Thus, d-Ala, and presumably other d-amino acids, have effects that are not merely consequences of their incorporation into PG. In this regard, d-amino acids likely regulate the periplasmic enzymes that synthesize and modify the PG polymer. We found that d- but not l-Met blocks the binding of a fluorescent derivative of penicillin G to several V. cholerae PBPs [77]. This result suggests that free amino acids accumulated in the periplasm might compete with muropeptide moieties for PBP active sites, thereby serving as regulators of PBP activity. While the exact identity of these PBPs remains to be determined, this observation suggests that d-amino acids may be direct modulators of PBP activity under stationary phase conditions. Further genetic and biochemical analyses of d-amino acid targets are necessary to define the mechanism(s) of d-amino acid action on cell wall PG.Fig. 4

Bottom Line: Many diverse bacterial phyla synthesize and release D-amino acids, including D-Met and D-Leu, which were not previously known to be made.These noncanonical D-amino acids regulate cell wall remodeling in stationary phase and cause biofilm dispersal in aging bacterial communities.Elucidating the mechanisms by which D-amino acids govern cell wall remodeling and biofilm disassembly will undoubtedly reveal new paradigms for understanding how extracytoplasmic processes are regulated as well as lead to development of novel therapeutics.

View Article: PubMed Central - PubMed

Affiliation: Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, and Howard Hughes Medical Institute, Boston, MA 02115, USA. fcava@rics.bwh.harvard.edu

ABSTRACT
The D-enantiomers of amino acids have been thought to have relatively minor functions in biological processes. While L-amino acids clearly predominate in nature, D-amino acids are sometimes found in proteins that are not synthesized by ribosomes, and D-Ala and D-Glu are routinely found in the peptidoglycan cell wall of bacteria. Here, we review recent findings showing that D-amino acids have previously unappreciated regulatory roles in the bacterial kingdom. Many diverse bacterial phyla synthesize and release D-amino acids, including D-Met and D-Leu, which were not previously known to be made. These noncanonical D-amino acids regulate cell wall remodeling in stationary phase and cause biofilm dispersal in aging bacterial communities. Elucidating the mechanisms by which D-amino acids govern cell wall remodeling and biofilm disassembly will undoubtedly reveal new paradigms for understanding how extracytoplasmic processes are regulated as well as lead to development of novel therapeutics.

Show MeSH
Related in: MedlinePlus