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Review
. 2025 Sep 2;15(9):1270.
doi: 10.3390/biom15091270.

Impact of D-Amino Acids in Schizophrenia

Serdar M Dursun  1 , Leman H Dursun  1 , Glen B Baker  1
Affiliations
Review

Impact of D-Amino Acids in Schizophrenia

Serdar M Dursun et al. Biomolecules. .

Abstract

Most amino acids contain a chiral center and thus, can exist as L- and D-isomers. For many years, it was thought that only the L-isomers were present in mammals. However, in recent decades it has been demonstrated that D-isomers are also present. Three of these amino acids, namely D-serine, D-aspartate, and D-alanine, have been proposed to play a role in the etiology of schizophrenia via interactions with glutamate receptors. D-Serine and D-alanine act at the glycine modulatory site on the NMDA receptor, while D-aspartate acts at the glutamate site on the same receptor. D-aspartate also acts on the mGlu5 receptor and can stimulate glutamate release presynaptically. Preclinical studies have reported that manipulations to reduce brain levels of D-serine, D-aspartate, or D-alanine lead to schizophrenia-relevant behaviors, and clinical studies have reported reduced levels of these D-amino acids in the brain tissue (postmortem) and/or body fluids from schizophrenia patients compared to those noted in controls, although there are some contradictory findings. The possible use of these amino acids and/or the manipulation of their relevant enzymes in the treatment of schizophrenia are described. D-Cysteine has been identified recently in human brain tissue, with the highest values in white matter; demonstration of its involvement in brain development has led to speculation that it could be involved in the etiology of schizophrenia, identifying it as a potential therapy in combination with antipsychotics. Future directions and potential problems that should be considered in studies on D-amino acids and their relevant enzymes in schizophrenia are discussed.

Keywords: D-alanine; D-amino acid oxidase; D-aspartate; D-aspartate oxidase; D-cysteine; D-serine; amino acids; schizophrenia; serine racemase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
Enzymatic pathway catalyzed by DAAO. Substrates include D-amino acids with small, neutral side chains such as D-serine, D-alanine, D-proline, and D-leucine [77]. FAD = flavin adenine dinucleotide. This figure was drawn using PowerPoint and was adapted based on information available in the literature (e.g. [32,77,78]).
Figure 1
Figure 1
Structure of D-serine. The structure was located by a Google search and drawn using ChemDraw (version 25.0).
Figure 3
Figure 3
Structure of D-aspartate. The structure was located by a Google search and drawn using ChemDraw (version 25.0).
Figure 4
Figure 4
Structure of D-alanine. The structure was located by a Google search and drawn using ChemDraw (version 25.0).
Figure 5
Figure 5
Structure of D-cysteine. The structure was located by a Google search and drawn using ChemDraw (version 25.0).
See this image and copyright information in PMC

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