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New Insights Into the Mechanisms and Biological Roles of D-Amino Acids http://www.diva-portal.org This is the published version of a paper published in Frontiers in Microbiology. Citation for the original published paper (version of record): Aliashkevich, A., Alvarez, L., Cava, F. (2018) New Insights Into the Mechanisms and Biological Roles of D-Amino Acids in Complex Eco-Systems Frontiers in Microbiology, 9: 683 https://doi.org/10.3389/fmicb.2018.00683 Access to the published version may require subscription. N.B. When citing this work, cite the original published paper. Permanent link to this version: http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-147303 fmicb-09-00683 April 3, 2018 Time: 15:53 # 1 REVIEW published: 06 April 2018 doi: 10.3389/fmicb.2018.00683 New Insights Into the Mechanisms and Biological Roles of D-Amino Acids in Complex Eco-Systems Alena Aliashkevich, Laura Alvarez and Felipe Cava* The Laboratory for Molecular Infection Medicine Sweden (MIMS), Department of Molecular Biology, Umeå University, Umeå, Sweden In the environment bacteria share their habitat with a great diversity of organisms, from microbes to humans, animals and plants. In these complex communities, the production of extracellular effectors is a common strategy to control the biodiversity by interfering with the growth and/or viability of nearby microbes. One of such effectors relies on the production and release of extracellular D-amino acids which regulate diverse cellular processes such as cell wall biogenesis, biofilm integrity, and spore germination. Non- canonical D-amino acids are mainly produced by broad spectrum racemases (Bsr). Bsr’s promiscuity allows it to generate high concentrations of D-amino acids in environments with variable compositions of L-amino acids. However, it was not clear until recent whether these molecules exhibit divergent functions. Here we review the distinctive biological roles of D-amino acids, their mechanisms of action and their modulatory Edited by: Jumpei Sasabe, properties of the biodiversity of complex eco-systems. Keio University, Japan Keywords: D-amino acids, D-methionine, D-arginine, bacteria, cell wall, Vibrio cholerae Reviewed by: Hiroshi Homma, Kitasato University, Japan INTRODUCTION Luke Moe, University of Kentucky, United States Amino acids have an a-carbon that is connected to four functional groups: an amine group *Correspondence: (−NH2), a carboxyl group (−COOH), a hydrogen (−H) and a side chain (−R). Therefore, the Felipe Cava a [email protected]; -carbon is a stereocenter (or chiral center) of the molecule since depending on the spatial [email protected] arrangement of these four different groups, two stereoisomers exist: the levorotatory (L) and the dextrorotatory (D). These stereoisomers are not superimposable mirror images to each other. Only Specialty section: in the particular case of glycine, there is a hydrogen atom as side chain −R, therefore glycine does This article was submitted to not have a chiral center. Microbial Physiology and Metabolism, L-Amino acids are essential for life since they provide the building blocks of proteins in all a section of the journal kingdoms of life. D-Amino acids (mainly D-alanine and D-glutamic acid) are also fundamental Frontiers in Microbiology in microbial physiology where they are key constituents of the peptidoglycan (PG) (Park and Received: 02 February 2018 Strominger, 1957; Hancock, 1960), an essential part of the bacterial cell wall. The presence of Accepted: 22 March 2018 D-amino acids in the peptide moieties of the PG of bacteria makes the cell wall invulnerable to Published: 06 April 2018 most proteases designed to cleave between L-amino acids. Additionally, the presence of alternative Citation: D-amino acids like D-Asp (Bellais et al., 2006; Veiga et al., 2006) or D-Ser at the terminal Aliashkevich A, Alvarez L and Cava F position of the stem peptide provides tolerance to certain bactericidal agents such as vancomycin (2018) New Insights Into the Mechanisms and Biological Roles (Sieradzki and Tomasz, 1996; Grohs et al., 2000; De Jonge et al., 2002; Reynolds and Courvalin, of D-Amino Acids in Complex 2005). Moreover, Lam et al.(2009) reported that diverse bacterial species produce and release Eco-Systems. Front. Microbiol. 9:683. to the environment different sets of D-amino acids (non-canonical D-amino acids or NCDAAs) doi: 10.3389/fmicb.2018.00683 in millimolar range concentration. In Vibrio cholerae, the production of D-amino acids in its Frontiers in Microbiology| www.frontiersin.org 1 April 2018| Volume 9| Article 683 fmicb-09-00683 April 3, 2018 Time: 15:53 # 2 Aliashkevich et al. Roles of D-Amino Acids stationary phase and their incorporation into the PG polymer Initially, this effect was reported to be due to D-amino acid control the strength and amount of this structure, thereby incorporation in the cell wall, which interfered with the proper providing fitness against low osmolarity and stationary phase localization of TapA (TasA anchoring/assembly protein), leading stresses such as starvation, growth arrest or accumulation of to the detachment of cell-anchored TasA amyloid fibers, the main secondary metabolites (Lam et al., 2009; Cava et al., 2011a). structural component of the fibrous biofilm’s scaffold produced Since this breakthrough, NCDAAs have been recognized by B. subtilis (Kolodkin-Gal et al., 2010; Romero et al., 2011). as a new type of bacterial effectors, produced by diverse However, later it was found that the B. subtilis strain used species, and whose biological roles are far from being fully in this study had a mutation in the dtd gene, the D-tyrosyl- defined. In fact, D-amino acids not only govern PG chemistry, tRNA deacylase that makes proteins refractive to D-amino acids’ density and strength in D-amino acid-producing and non- incorporation (Leiman et al., 2013). Complementation with the producing bacteria (Cava et al., 2011a), but also regulate spore wild-type Dtd enzyme made the B. subtilis resistant to the biofilm germination and biofilm dispersal in certain species (Hills, 1949; dissociating activity of D-amino acids and thus, Kolodkin-Gal Bucher et al., 2015). D-Amino acids are produced by both et al.(2010) article has raised a great interest and controversy highly specific and broad spectrum racemases (Bsr) in bacteria regarding if and how D-amino acids can influence biofilm (reviewed in detail by Hernández and Cava, 2016). Conversely to stability in different bacteria. For example, Kao et al.(2017) monospecific racemases, Bsr are able to produce D-amino acids showed that Pseudomonas aeruginosa PAO1 biofilm formation is from a wide range of both proteinogenic and non-proteinogenic not inhibited by D-Trp (10 mM) and D-Tyr (10 and 1 mM), while L-amino acids (Espaillat et al., 2014). Bsr-containing bacteria Rumbo et al.(2016) reported biofilm inhibition in the same strain are, in general, Gram-negative bacteria associated to various by 4 mM D-Trp (10% biofilm reduction) and 4 mM D-Tyr (16% environments like soil, water or animal hosts. Availability and biofilm reduction) using similar methodologies. identity of L-amino acids in those environments would affect the A similar situation was observed for Staphylococcus aureus. final composition and amount of the D-amino acids. Hochbaum and colleagues found that S. aureus SC01 biofilm In this review, we focus on the molecular mechanisms and formation was efficiently inhibited by 500 mM of either D-Tyr, the ecological consequences that the environmental release of D-Pro or D-Phe, while a mixture of these three D-amino acids D-amino acids causes in microbial communities and the host was already effective at less than 100 mM(Hochbaum et al., (Figure 1). 2011). D-Amino acids did not prevent the initial attachment of the bacterial cells to the surface, but inhibited subsequent growth of the initial microcolonies into larger assemblies by ROLE OF D-AMINO ACIDS IN affecting the protein component of the EPS. Production and MICROBIAL COMMUNITIES localization of exopolysaccharide was not significantly affected. The D-amino acid mixture was also able to disassemble already Biofilm Dispersal by D-Amino Acids existing S. aureus biofilms, but at much higher concentration In the environment, bacteria exist in planktonic and biofilm (10 mM). On the contrary, Sarkar and Pires(2015) reported state. Biofilms are bacterial communities held together by that S. aureus SC01 biofilm formation was not inhibited by D- a self-produced extracellular polymeric substance (EPS), Tyr or D-Tyr/D-Pro/D-Phe mix even though the authors used which is typically composed of protein, exopolysaccharide millimolar concentrations in the study. and often extracellular DNA (Branda et al., 2005; Flemming A similar mechanism of biofilm disassembly as in B. subtilis and Wingender, 2010). In the biofilm, bacteria are effectively has been suggested for Staphylococcus epidermidis. The biofilm of protected from harmful environmental threats, and persister S. epidermidis contains polysaccharides and proteins such as Aap, cells can develop upon antibiotic attack. These cells can re- which has a PG binding motif and undergoes polymerization to emerge once the environment becomes more favorable thereby form fibers (Rohde et al., 2005). The authors hypothesize that the contributing to chronic infections (Lam et al., 1980; Costerton, polymerization ability of Aap is affected by D-amino acids, which 1999; Singh et al., 2000; Post, 2001) and making eradication of ultimately leads to biofilm disassembly. Different sensitivity to biofilms a serious health care issue (Lewis, 2001). Therefore, D-amino acids during biofilm formation has been demonstrated interfering with biofilm formation or stimulating its dissociation for a wide set of pathogenic and non-pathogenic S. epidermidis is an attractive strategy to combat bacterial infections and strains (Ramon-Perez et al., 2014). For some strains, biofilm preventing their chronic development. However, biofilms are formation was reduced by all D-amino acids tested (D-Leu, D- not just a major problem in clinics, but also in agriculture Tyr, D-Pro, D-Phe, D-Met, and D-Ala), while only some specific because of plant loss due to bacterial diseases (Ramey et al., 2004; D-amino acids or none had an inhibitory effect in other strains.
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