D-Amino Acids in Neurotransmission and Bacterial Metabolism

D-Amino acids, once regarded as rare curiosities, are now recognised as pivotal modulators in both neuronal signalling and microbial physiology. In the central nervous system, D-serine and D-aspartate serve as co-agonists at N-methyl-D-aspartate (NMDA) receptors, finely tuning synaptic plasticity, learning and memory. Their levels are governed by the antagonistic activities of serine racemase, which converts L-serine into D-serine, and D-amino acid oxidase, which degrades D-serine. Dysregulation of these enzymes and altered D-amino acid pools have been implicated in psychiatric disorders, cognitive ageing and neurodegeneration, highlighting therapeutic and biomarker potential. In parallel, bacteria deploy a repertoire of broad-spectrum racemases to generate non-canonical D-amino acids that integrate into the peptidoglycan cell wall, remodel biofilms and mediate interspecies competition within complex ecosystems. These bacterial D-amino acids act as extracellular effectors, influencing spore germination, cell-wall integrity and community dynamics with far-reaching implications for antibiotic resistance and microbiome engineering. Recent advances in analytical chemistry and fluorescent probes now enable chiral-specific detection of D-amino acids in tissues, fluids and living cells, facilitating the elucidation of their spatial and temporal dynamics across health, disease and environmental contexts.

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D-Amino Acids in Neurotransmission and Bacterial Metabolism publication trend

The graph below shows the total number of articles in d-amino acids in neurotransmission and bacterial metabolism across all publications each year (not limited to Nature Index journals).

Technical terms

D-Amino acid: One of two mirror-image forms (enantiomers) of an amino acid, differing from the more common L-form by spatial configuration around the α-carbon.

Serine racemase: An enzyme that converts L-serine to D-serine, modulating co-agonist availability at NMDA receptors.

D-amino acid oxidase: A flavoprotein that catalyses oxidative deamination of D-amino acids, regulating their tissue concentrations.

N-methyl-D-aspartate (NMDA) receptor: A subtype of ionotropic glutamate receptor that requires glutamate and a co-agonist (such as D-serine) for activation, crucial for synaptic plasticity.

Broad-spectrum racemase: A bacterial enzyme capable of converting multiple L-amino acids into their D-forms, contributing to cell-wall architecture and community signalling.

Peptidoglycan: A polymeric mesh of sugars and amino acids forming the rigid bacterial cell wall, whose composition can be modulated by incorporation of D-amino acids.

References

1. Neuron-derived D-Serine Release Provides a Novel Means to Activate N-Methyl-D-aspartate Receptors*. Journal of Biological Chemistry (2006).
2. Serine Racemase Modulates Intracellular D-Serine Levels through an α,β-Elimination Activity*. Journal of Biological Chemistry (2004).
3. Blood levels of D-amino acid oxidase vs. D-amino acids in reflecting cognitive aging. Scientific Reports (2017).
4. D-Serine: Potential Therapeutic Agent and/or Biomarker in Schizophrenia and Depression?. Frontiers in Psychiatry (2019).
5. The Role of Amino Acids in Neurotransmission and Fluorescent Tools for Their Detection. International Journal of Molecular Sciences (2020).
6. Emerging knowledge of regulatory roles of d-amino acids in bacteria. Cellular and Molecular Life Sciences (2010).
7. New Insights Into the Mechanisms and Biological Roles of D-Amino Acids in Complex Eco-Systems. Frontiers in Microbiology (2018).