Distinctive Roles of D-Amino Acids in the Homochiral World: Chirality of Amino Acids Modulates Mammalian Physiology and Pathology

Abstract

Living organisms enantioselectively employ L-amino acids as the molecular architecture of protein synthesized in the ribosome. Although L-amino acids are dominantly utilized in most biological processes, accumulating evidence points to the distinctive roles of D-amino acids in non-ribosomal physiology. Among the three domains of life, bacteria have the greatest capacity to produce a wide variety of D-amino acids. In contrast, archaea and eukaryotes are thought generally to synthesize only two kinds of D-amino acids: D-serine and D-aspartate. In mammals, D-serine is critical for neurotransmission as an endogenous coagonist of N-methyl D-aspartate receptors. Additionally, D-aspartate is associated with neurogenesis and endocrine systems. Furthermore, recognition of D-amino acids originating in bacteria is linked to systemic and mucosal innate immunity. Among the roles played by D-amino acids in human pathology, the dysfunction of neurotransmission mediated by D-serine is implicated in psychiatric and neurological disorders. Non-enzymatic conversion of L-aspartate or L-serine residues to their D-configurations is involved in age-associated protein degeneration. Moreover, the measurement of plasma or urinary D-/L-serine or D-/L-aspartate levels may have diagnostic or prognostic value in the treatment of kidney diseases. This review aims to summarize current understanding of D-amino-acid-associated biology with a major focus on mammalian physiology and pathology.

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…These two faces of the glutamate‐NMDA receptor's nature make it difficult to use NMDA antagonists as neuroprotective agents against stroke and neurodegenerative diseases, even though NMDA blockers do exert strong neuroprotection . Another aspect of the NMDA receptor is the discovery of co‐agonists that work in concert with glutamate . At present, two different co‐agonists have been identified: D‐serine and glycine.…”

“…SRR is almost exclusively expressed in pre‐synaptic neurons, indicating that pre‐synaptic neurons release both glutamate and D‐serine into the synaptic cleft and modulate postsynaptic function (Fig. ) . Of note, L‐serine is more abundant in astroglia than in neurons.…”

“…148,149 Another aspect of the NMDA receptor is the discovery of co-agonists that work in concert with glutamate. [150][151][152][153][154][155] At present, two different coagonists have been identified: D-serine and glycine. The former acts as a co-agonist of glutamate in synaptic NMDA receptors, and the latter acts in extra-synaptic NMDA receptors.…”

“…8). 155,156 Of note, L-serine is more abundant in astroglia than in neurons. The de novo synthesis of L-serine occurs exclusively in astroglia, and its synthetic pathway branches at glycolysis, implying the presence of another metabolic compartment between neurons and astroglia (Fig.…”

d-Amino acids and kidney diseases

“…DAO activity is also detected in the neutrophils, retina, and the small intestine in mouse. The complemental distribution of SR and DAO in the brain may determine the heterogenic distribution of d-serine [31].…”