d-amino acids: new functional insights

The d-enantiomers of amino acids (d-AAs) were initially considered "unnatural" molecules. They are primarily of microbial origin, present in low amounts, and without biological functions in eukaryotes. However, over the past few decades, sensitive analytical methods have uncovered the presence of both free and peptide-bound d-AAs in higher organisms. During the same period, the discovery of serine racemase-the enzyme that catalyzes the reversible formation of d-serine from l-serine-in rat brains demonstrated that mammals synthesize d-AAs. Notably, the enzymes responsible for d-AAs catabolism were identified almost 90 years ago. Subsequently, free d-AAs such as d-serine, d-aspartate, d-alanine, and d-cysteine have emerged as a novel and important class of signaling molecules in various organs, including the brain and endocrine system. Their involvement in a wide range of neurological disorders has drawn significant scientific interest. We have focused on novel findings, based on the latest analytical techniques, that have reshaped our understanding of physiological processes across diverse organisms, from plants to humans. Beyond neurotransmission, recent studies have highlighted the versatile roles of d-AAs in cancer, inflammation, immune regulation, kidney disease, and diabetes. Moreover, these studies suggest that the levels of d-AAs in blood and urine could serve as early biomarkers for conditions such as Alzheimer's disease, schizophrenia, and chronic kidney disease. Understanding the role of d-AAs in certain pathological states is helping to identify new therapeutic targets, offering promising opportunities for clinical applications in treating various diseases.