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.

Introduction

Chirality is a property of objects that are non-superimposable on their mirror image. The two forms of a chiral object are called enantiomers. Many living organisms possess macroscopic chirality, e.g. the shells of most snails form right-handed spirals. Human morphology also has chirality: the heart is located on the left side and the liver is arranged on the right.

The concept of molecular chirality has fascinated scientists since Pasteur first separated enantiomeric crystals of tartaric acid more than 150 years ago. The right-handed (dextro-: D-enantiomer) and left-handed molecule (levo-: L-enantiomer) have identical molecular mass with equivalent chemical and physical energy, but the manner in which they interact with other molecules is different, just as a right hand interacts differently with left- and right-hand gloves (Fig. 1). Mysteriously, living organisms utilize only a single enantiomer in each biological process. There are two major facts relating to the single chirality of biological molecules: most sugars are D-sugars and most amino acids are L-amino acids. Without some type of chiral influence, a chemical reaction that makes a product with a chiral center will always yield equal amounts of D- and L-enantiomers (called a racemic mixture), and, therefore, it is considered that sugars and amino acids were racemic in primordial Earth before the emergence of life. Although the processes that changed the initially racemic world and how such bias was sustained and propagated into the current homochiral world remain controversial (nicely reviewed by Blackmond),¹ biological evolution resulted in the exclusive use of L-amino acids in ribosomal protein synthesis and D-sugar (D-ribose) in nucleotides. The resulting homochirality enables consistent protein foldings and forms the immutably right-handed helix of DNA. Because the aminoacylation of transfer RNA is the first step of ribosomal protein synthesis, this reaction could have provided the chiral selectivity of amino acids in protein. Interestingly, there is a clear preference of L-amino acids for nonprotein RNA-directed aminoacylation of RNA minihelices composed of D-ribose as the sugar backbone, and a mirror-image RNA system shows the opposite selectivity.² Therefore, the L-amino acid homochirality of proteins could be determined by the homochirality of RNA, which has a D-ribose configuration. RNA chirality may, in turn, have been influenced by prebiotic amino acids that were chiral catalysts for the synthesis of D-sugars.³ Although the mechanism underlying the initial imbalance of D-/L-amino acids or D-/L-sugars on the primordial Earth is not understood, D-amino acids and L-sugars were selectively excluded from living systems after a long chain of events that might constitute an essential process for the development and maintenance of life. Consequently, it was initially believed that only a single enantiomer of each class of compounds occurred in nature, and L-sugars and D-amino acids were regarded as laboratory artifacts and categorized as “unnatural isomers”; however, this is not in fact the case.

Fig. 1

. D- and L-configurations of a chiral amino acid. R is the side chain of the amino acid.

1. D-Amino Acids in the Domain Bacteria

Bacteria were among the first life forms to appear on Earth and have the largest genetic capacity to metabolize D-amino acids. D-Amino acids are utilized as nutrients to support bacterial growth,^4,5,6,7 to regulate bacterial spore germination,^8,9,10 and as components of bacterial cell walls¹¹ and some bacterial peptide antibiotics¹² (Fig. 2). The discovery by Snell in 1945 that D-Ala is a growth factor in the absence of vitamin B6 for Streptococcus faecalis and Lactobacillus casei^13,14 led to a series of studies which ultimately revealed the essential requirement of D-Ala as a component of peptidoglycan found in the cell walls of virtually all bacteria. D-Ala and D-Glu are by far the most common D-amino acids present in the bacterial cell wall; however, the peptidoglycan of some bacteria includes other D-amino acids, such as D-Asp in Lactococcus¹⁵ and Enterococcus,¹⁶ and D-Ser in vancomycin-resistant Staphylococcus aureus.^17,18,19 These D-amino acids are synthesized by amino acid racemases – enzymes that catalyze the stereochemical inversion of biological molecules. To date, more than 10 kinds of racemases have been identified in bacteria.²⁰ The resulting D-amino acids may be incorporated into the peptides via a non-ribosomal peptide (NRP) synthetic pathway that generates peptides independent of the chiral selection of amino acids by transfer RNA. The presence of D-amino acids in peptidoglycan contributes to cross-linking repeated disaccharide units that form a mesh-like architecture and provides resistance to most known proteases.²¹ Recently, it has become clear that various free D-amino acids, including D-Met, D-Leu, D-Tyr, and D-Phe, are also synthesized and released by bacteria from diverse phyla at up to millimolar concentrations.²² Furthermore, these released D-amino acids function to regulate cell wall chemistry and architecture²² as well as to promote biofilm development in bacteria.²³

Fig. 2

. Cell walls of bacteria, archaea, and eukaryotes. D-Amino acids are integral components of bacterial cell walls but are not used in those of archaea or eukaryotes. Chloroplasts and mitochondria are essential eukaryotic organelles of endosymbiotic origin that arose from an alpha-proteobacterial or a cyanobacterial ancestor. Bacterial genes to synthesize D-amino acids were subjugated by the host cells, and the peptidoglycan layers of those ancestors are not found in the organelles.

2. D-Amino Acids in the Domain Archaea

In contrast to the relative abundance of D-amino acids in bacteria, much fewer studies have reported the occurrence of D-amino acids in archaea. Archaea form one of three domains of life and are a group of single-celled prokaryotic organisms predominantly with a cell wall. Among the distinct molecular characteristics that differentiate archaea from bacteria, one is the composition of the cell wall (Fig. 2). Whereas peptidoglycan is a standard component of all bacterial cell walls, archaeal cell walls lack peptidoglycan, with the exception of some methanogens, such as Methanobacteriales and Methanopyrus.²⁴ The cell walls of these exceptional groups of archaea are composed of a peptidoglycan-like structure, called pseudopeptidoglycan, which has a similar physical structure to that of bacterial peptidoglycan but includes cross-linking peptides made up of only L-amino acids.²⁵ Therefore, archaea do not utilize D-amino acids as building blocks for their cell walls. However, there are several reports of the occurrence of D-amino acids in archaea, such as D-Asp in some hyperthermophilic archaea^26,27 and in Thermoplasma acidophilum,²⁸ and D-Ser in Pyrobaculum islandicum,²⁹ although their functions are not well understood. A more recent report states that Pyrococcus horikoshii, a hyperthermophilic archeon, metabolizes several D-amino acids with a broad-spectrum racemase for their growth,³⁰ suggesting that a group of archaea fully utilizes D-amino acids as nutrients obtained in the extreme environments in which they live.

3. D-Amino Acids in the Domain Eukaryotes

Eukaryotes are considered to be a sister group of archaea and are phylogenetically distant from bacteria.³¹ Unsurprisingly, the overall capacity of D-amino acid metabolism in eukaryotes is much smaller than that in bacteria, just as it is in archaea. Eukaryotic cell walls, such as those of plants and fungi, are basically made of polysaccharides and do not include D/L-amino acids (Fig. 2). Furthermore, some organelles, such as mitochondria and chloroplasts, are generally accepted to be descendants of endosymbiotic bacteria, but their peptidoglycan is vestigial or absent in eukaryotic cells, with the rare exception of a small group of primitive algae called glaucophytes.³² Therefore, eukaryotic D-amino acids are important only in non-cell-wall associated biological processes.

3.1. D-Amino acids in the animal kingdom of eukaryotes

A few kinds of D-amino acids, mainly D-Ala/D-Ser/D-Asp, have been detected in a variety of eukaryotes as free amino acids or, rarely, as components of peptides and proteins.^33,34 The first free D-amino acid detected in animals was D-Ala found by Auclair and Patton in the 1950s in the blood of the milkweed bug Oncopeltus fasciatus.³⁵ This was followed by the discovery in the 1960s of free D-Ser in the earthworm and silkworm Bombyx mori.^36,37,38 In the 1970s and 1980s, millimolar levels of D-amino acids were detected in aquatic invertebrates: D-Asp (>50% of total Asp) in the brain of Octopus vulgaris,³⁹ D-Ala (30–50% of total Ala) in muscle and hepatopancreas of aquatic crustaceans,^40,41 and D-Ala (>50% of total Ala) in heterodont bivalve mollusks ,^42,43 in which D-Ala works as a major osmolyte allowing adaptation to a changing external osmotic environment.^44,45

Whereas D-amino acids are routinely incorporated into peptides in the bacterial cell wall, peptides that contain D-amino acids are unusual in eukaryotes. Short peptides, called dermorphin, dermenkephalin, or deltorphins, have been isolated from skin secretions of the Argentinian tree frog Phyllomedusa sauvagei. These short peptides contain D-Ala or D-Met in the second position and have selective affinity for opioid receptors.^46,47,48,49 Two short peptides, called achatin-I and fulicin, have been isolated from African snail Achatina fulica and include D-Phe and D-Asn at the second position in the respective peptides, both of which function as excitatory neurotransmitters controlling heart beat or penis contraction.^50,51,52 Further examples of D-amino acid-containing eukaryotic peptides include FRF peptides in Aplysia,⁵³ contryphans in cone snails,⁵⁴ and omega-agatoxin in funnel-web spiders.⁵⁵ How D-amino acids are introduced to such peptides remains largely unknown, but it is assumed to be mediated through either NRP pathways or post-translational modifications of ribosomal peptides such as by enzymatic peptide isomerization.³⁴ It is notable that such isomerization potentiates the functional activity of these peptides and prevents their degradation by most peptidases and proteases.

3.2. Intrinsic D-amino acids in mammals

Substantial levels of free D-Asp and D-Ser occur in mammals, especially in nervous and endocrine tissues.

3.2.1. Physiological role of D-aspartate in mammals: neurogenesis and endocrine system

The first discovery of D-amino acids in mammals was that of free D-Asp by Dunlop et al. in 1986.⁵⁶ To date, D-Asp has been described in the brain, neuroendocrine system, and testis of mammals, specifically in rats, Rattus norvegicus;^56,57,58,59 mice, Mus musculus;⁶⁰ and humans, Homo sapiens.^61,62,63 Notably, D-Asp occurs spatiotemporally in the brain; its level peaks with the expansion of neocortical neuroepithelium in early embryonic development and levels fall drastically after birth, supporting the idea that D-Asp plays a role during development and neurogenesis.^64,65 Because D-Asp has a relatively high affinity for the L-Glu binding site of N-methyl-D-aspartate glutamate receptors (NMDAR),^66,67,68 increased D-Asp modulates age-related hippocampal synaptic plasticity, dendritic morphology, and spatial memory.^69,70,71 Moreover, in rodent endocrine tissues, particularly in pituitary, pineal, and adrenal glands and testis, D-Asp levels increase temporarily at the specific stages after birth in concomitance with their functional maturation. Consequently, the appearance of D-Asp has been functionally correlated with the synthesis or the release of various hormones in rodents.^72,73 As for D-Asp metabolism, a mammalian peroxisomal flavoenzyme, D-aspartate oxidase (DDO), catalyzes oxidative deamination of D-Asp and D-Glu.^74,75 In Ddo knockout mice compared to wild-type mice, D-Asp levels in adults are increased more than 10-fold in almost all tissues.^76,77 Therefore it can be concluded that D-Asp levels are widely and physiologically regulated in vivo by DDO. In contrast, only trace levels of D-Glu were found in Ddo knockout mice and levels were comparable to those in wild-type animals. Consequently, D-Glu was not considered to circulate or to be metabolized in rodents (mammals).⁷⁷ More recently, however, mammalian mitochondrial protein 9030617O03Rik, expressed mainly in the heart and kidney, was shown to have activity as a D-Glu cyclase that converts D-Glu to 5-oxo-D-proline. Systemic 9030617O03Rik knockout mice had a small accumulation of D-Glu in the heart, although the origin of the amino acid and the physiological role of the protein is not yet understood.⁷⁸ Another aspect of Ddo knockout studies is the indication of a mammalian D-Asp synthetic pathway: the increased D-Asp levels in the Ddo knockout mice are similar to or even higher in some regions than the L-Asp levels in those mice,⁷⁷ which could not occur without de novo synthesis of D-Asp by endogenous enzymes. Indeed, glutamic-oxaloacetic transaminase-1 like 1 (Got1l1) was identified as a putative aspartate racemase and is involved in adult neurogenesis.⁷⁹ A later study, however, demonstrated that systemic knockout of Got1l1 in mice does not alter the level of D-Asp in the brain or testis,⁸⁰ indicating the presence of an unknown authentic synthetic enzyme in mammals. Interestingly, recent studies suggest that mammalian serine racemase (SR), an endogenous synthetic enzyme for D-Ser,⁸¹ is involved, at least in part, in D-Asp synthesis in the brain but not in the testis.^82,83 Notably, the findings of these studies are supported by phylogenetic and biochemical analyses in various invertebrates indicating that SR and aspartate racemase form a serine/aspartate racemase family, and that some invertebrate SR also has mild aspartate racemase activity.⁸⁴ Given that SR mediates some portion of D-Asp production in the brain, further studies are needed to understand the synthetic pathways responsible for the rest of the D-Asp found in the brain as well as in the endocrine tissues.

3.2.2. Physiological role of D-serine in mammals: neurotransmission

D-Ser is another major D-amino acid found in mammals. It is the most studied D-amino acid in mammals in terms of biochemistry, physiology, and pathology. Free D-Ser was first described in rat brain by Hashimoto et al. in 1992.⁸⁵ D-Ser is detected at submillimolar levels (10–30% of total serine), especially in the forebrain area, in virtually all tested mammals, including primates. However, D-Ser has not been detected in fish, amphibians, or birds,^86,87,88,89 which supports the view that brain D-Ser is conserved in mammals and that this is evolutionally distinct from the other classes of vertebrates (Fig. 3). Non-mammalian vertebrates highly express D-serine dehydratase, a PLP-dependent enzyme with beta elimination activity, in the brain.⁹⁰ This enzyme actively degrades D-Ser and effectively clears it in those animals. The primary difference between mammalian and non-mammalian brains is the presence of cerebral neocortex. The emergence of D-Ser in the mammalian forebrain may therefore represent the functional evolution of cerebrum in mammals. Indeed, the “old” brain areas such as the brainstem and cerebellum contain D-Ser at levels less than 1/10 of those found in the cerebrum in mammals.^88,89

Fig. 3

. Distribution of D-Ser in the central nervous systems of vertebrates. Typical vertebrate brain structures are shown with the cerebrum highlighted in ocher. D-Ser (red dots) occurs exclusively in mammalian (including human) cerebrum.

The forebrain-shifted distribution of D-Ser is determined by the activities of two principal enzymes: SR and D-amino acid oxidase (DAO). D-Ser is converted from L-Ser by SR, which was first purified by Wolosker in 1999.⁸¹ Currently, SR is the only amino acid racemase identified in mammals and is predominantly expressed in excitatory neurons located in the forebrain.^91,92,93 However, the primary site of synthesis and release of D-Ser remains controversial.⁹⁴ SR catalyzes both the racemization and the α,β-elimination of serine enantiomers⁹⁵ and therefore has ability to both synthesize and degrade D-Ser. Wolosker proposed an astrocyte–neuron communication model in the forebrain area involving the exchange of serine enantiomers, called “the serine shuttle,” whereby astrocytes synthesize and export the L-Ser required for the synthesis of D-Ser by the predominantly neuronal SR.⁹⁶ Neuronal and glial D-Ser production depends on the L-Ser produced by the astrocytic enzyme 3-phosphoglycerate dehydrogenase.⁹⁷ Another key enzyme for D-Ser regulation is the flavoenzyme DAO. DAO was first discovered in the porcine kidney by Krebs in 1935,⁹⁸ but its physiological role was not well understood until the discovery of D-Ser in the mammalian brain in the 1990s. DAO catabolizes neutral and basic D-amino acids, including D-Ser, through oxidative deamination. Whereas the majority of SR is detected in the forebrain, DAO activity in the central nervous system is restricted to astrocytes in the hindbrain and spinal cord in rodents.^99,100,101 This differential distribution of SR and DAO determines the forebrain-shifted distribution of D-Ser. The knockout of SR in mice reduces the level of D-Ser in the forebrain by 90%. However, the loss of DAO activity does not affect the regional level of D-Ser,^102,103 indicating that SR is the major regulator of D-Ser in the forebrain. In contrast, in the hindbrain and spinal cord, DAO plays a crucial role in maintaining D-Ser at a low level (~5 nmol/g in the mouse cerebellum) because the loss of DAO activity increased the regional level of D-Ser by more than 20-fold.^103,104 The increased D-Ser level in the hindbrain of DAO-null mice was reduced by 1/2–1/3 in that of double mutant mice that lacked both SR and DAO.¹⁰³ This finding indicates that DAO degrades D-Ser produced by SR in the hindbrain area. Given that neuronal SR is the primary source of D-Ser, D-Ser should be actively taken up by astrocytes in the hindbrain, although the uptake mechanism is unclear. In summary, D-Ser is actively produced and maintained at a high level by SR, especially in the evolutionally “new brain,” but is cleared by DAO in the “old brain” in mammals.

The functional role of D-Ser in the forebrain has been intensively studied for more than a decade. D-Ser has an enantioselective affinity to a coagonist-binding site of the GluN1 subunit of NMDAR,¹⁰⁵ to which glycine also has high affinity. NMDAR is one of the ionotropic glutamate receptors, but it is distinct from the other receptors, such as alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid or kinate receptors, in its essential requirement of coagonist binding in addition to glutamate to be activated. Because D-Ser was not thought to exist in mammals, glycine was initially considered to be the coagonist of NMDAR in mammals. Although glycine is far more abundant than D-Ser in the mature mammalian brain, and although both amino acids have a very similar high affinity to the coagonist-binding site, D-Ser is now regarded as the endogenous coagonist for NMDAR¹⁰⁶ because genetic disruption of SR reduces synaptic NMDAR currents and impairs synaptic plasticity in rodents.^92,102 Intriguingly, a seminal study by Papouin et al.¹⁰⁷ demonstrated, using hippocampal synapses, that D-Ser gates preferentially synaptic GluN2A-NMDARs, whereas glycine targets extrasynaptic receptors. Because the distribution patterns of SR and D-Ser correspond closely to that of GluN2A/B subunits of NMDAR in rodents and humans,^{89,91,108,109} widespread distribution of glycine may suggest additional roles of glycine, such as through inhibitory glycine receptors. Considering that D-Ser, compared to glycine, has three additional hydrogen bonds to the coagonist-binding site,¹¹⁰ the emergence of D-Ser in the evolved cerebrum might have enabled efficient activation of NMDAR in the functionally diverse mammalian brain.

Another role of D-Ser as a neuromodulator is known in the cerebellum during the early postnatal period. Although glial DAO activity maintains cerebellar D-Ser at a low level in adults, D-Ser is observed at high concentrations during the development of the cerebellum. Indeed, DAO activity is biochemically undetected in the cerebellum in rodents until 14 days after birth.¹¹¹ Unlike in the forebrain, where D-Ser regulates postsynaptic NMDARs, in the immature cerebellum, D-Ser serves as an endogenous ligand for the delta2 glutamate receptor (GluD2) to regulate long-term depression (LTD) at synapses between parallel fibers and Purkinje cells.¹¹² GluD2, encoded by Grid2, is a member of the ionotropic glutamate receptor family and is selectively expressed in cerebellar Purkinje cells. Grid2-null mice show impaired LTD and severe motor dyscoordination,¹¹³ suggesting a critical role of GluD2 in cerebellar functions. Importantly, mice expressing mutant GluD2 with a disrupted binding site for D-Ser show impaired LTD and motor dyscoordination during development,¹¹² which therefore suggest that the transient D-Ser surge in the immature cerebellum is involved in the acquisition of motor coordination and improves learning efficiency in childhood.

3.2.3. Metabolic disorder of intrinsic D-amino acids: psychiatric and neurological diseases

Intrinsic D-amino acids such as D-Ser and D-Asp are likely involved in pathologies associated with NMDAR dysfunction. Optimal NMDAR activity is crucial for neuronal homeostasis, and altered NMDAR activity is implicated in multiple conditions, including aging, neurodegeneration, and neuropsychiatric disorders.^105,114 As an endogenous coagonist of NMDARs, D-Ser plays a role in NMDAR neurotoxicity in which overstimulation of NMDARs evokes excessive firing of neurons. Degradation of D-Ser by externally added D-Ser deaminase (a bacterial D-serine-degrading enzyme) in slice-culture settings,¹¹⁵ and SR-knockout in mice, strikingly alleviate NMDAR-mediated neurotoxicity.¹¹⁶ These findings show that regulation of D-Ser is crucial for neurons to maintain their physiological level of excitability. Compared to wildtype mice, SR-knockout mice show reduced ischemic damage (which involves excessive firing of neurons in peri-ischemic lesion) induced by middle cerebral artery occlusion.^117,118 D-Ser also seems to play a role in epilepsy, evidenced by the fact that SR-knockout mice are partially resistant to seizures induced by pentylenetetrazol, a GABA antagonist.¹¹⁹ Furthermore, metabolic disorders of D-Ser have been implicated in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS).^120,121,122 ALS is the most common motor neuron disease and is clinically characterized by the coexistence of upper and lower motoneuronal signs with progressive neurological deterioration.¹²³ Classically, motoneurons are known to be vulnerable to glutamate excitotoxicity, which has long been implicated in sporadic and familial ALS.^124,125 Currently, the evidence that strongly links D-Ser to ALS pathology is as follows: (i) D-Ser accumulates in the spinal cord of an animal model of ALS (superoxide dismutase 1 G93A transgenic mice) mainly as a result of down-regulation of DAO in activated glial cells^126,127; (ii) dominant negative mutation D199W in DAO causes familial ALS that exhibits the adult-onset ALS phenotype with rapid progression¹²⁸; (iii) ALS-associated mutant HNRNPA2B1 results in the skipping of an exon in DAO, and this significantly reduces DAO activity¹²⁹; (iv) D-Ser is toxic to motoneurons, potentially through the enhancement of glutamate excitotoxicity,¹²⁶ NMDA-receptor-related acceleration of autophagy,¹²¹ or both; and (v) lack of DAO activity caused by point mutation G181R¹²⁷ or overexpression of human R199W-DAO¹³⁰ triggers mild motoneuronal degeneration in mice. Considering that D-Ser is physiologically maintained at a low level by DAO activity in the motor pathway,¹⁰¹ it is plausible that accumulation of D-Ser may lead to NMDAR-mediated neurotoxicity, which may contribute to the progression and/or onset of ALS.¹³¹ However, because the clinical presentation of ALS is heterogeneous and the pathogenesis of ALS is a multistep process,¹³² it remains unclear to what extent ALS pathogenesis involves D-Ser accumulation. Therefore, whether modulation of D-Ser has therapeutic benefits for ALS patients warrants further examination.

In addition to the involvement of D-Ser in neurotoxicity, altered D-Ser synthesis or metabolism may play a role in schizophrenia. Schizophrenia is a severe chronic mental disorder that results from a combination of environmental insults and genetic vulnerabilities, in which dysfunction of NMDAR is one of the core hypotheses.^{133,134,135,136} A meta-analysis of 20 studies regarding the association of D-Ser with schizophrenia showed that D-Ser levels in the serum were significantly decreased in patients with schizophrenia, especially in male patients.¹³⁷ Systematic unbiased meta-analysis of genetic association studies revealed that DAO and several NMDAR-associated genes showed significant effects as risk factors for schizophrenia.¹³⁸ Furthermore, the largest genome-wide association study of schizophrenia to date identified independent associations implicating numerous brain-enriched genes, including SR and several other genes related to glutamatergic transmission.¹³⁹ Importantly, SR-knockout mice recapitulate many of the structural and molecular brain abnormalities, as well as the cognitive deficits, associated with schizophrenia.^102,140 In contrast to the genetic implications, the molecular mechanisms by which D-Ser is reduced in the context of NMDAR hypofunction in schizophrenia remains largely obscure. Notably, mice harboring mutant disrupted-in-schizophrenia 1, a gene truncated in a large family with major psychiatric disorders, exhibit lower brain D-Ser levels as a result of increased SR degradation and have the abnormalities associated with NMDAR hypofunction.¹⁴¹ Clinical evidence to extensively support the idea that lower D-Ser levels underly NMDAR hypofunction¹⁴² includes the fact of therapeutic benefit with D-Ser supplementation in addition to antipsychotics, especially for negative and cognitive symptoms of patients with schizophrenia.^143,144 Large phase II trials testing the efficacy of D-Ser for treating schizophrenia and the schizophrenia prodrome are ongoing, both as an add-on to treatment with antipsychotics and as monotherapy. Several research groups have focused on using DAO inhibitors as another approach to the treatment of schizophrenia.¹⁴⁵ DAO inhibition reportedly increases hippocampal NMDAR-associated current in rodents.^146,147 Although DAO activity is not detected in the rodent forebrain area, systemic DAO inhibition may potentially affect the activity of NMDAR by increasing systemic D-Ala,¹⁰⁰ which has a relatively high affinity for the D-Ser-binding site of NMDAR.¹⁴⁸ Moreover, treatment with antipsychotics and D-Ala improved the negative symptoms of patients with schizophrenia.¹⁴⁹ To date, more than 500 compounds have been shown to inhibit DAO activity in vitro and/or in vivo.^145,150 Additional approaches to the regulation of synaptic D-Ser, such as blocking its uptake or modulating SR, for treatment of schizophrenia also await future studies.

In addition to D-Ser, another intrinsic D-amino acid, D-Asp, may play a role in the pathology of schizophrenia as an agonist of the L-Glu binding site of NMDAR. D-Asp is protective against prepulse inhibition deficits in mice with psychological abnormality induced by NMDAR antagonists amphetamine, MK-801, and phencyclidine.^69,151 Such prepulse inhibition deficits are also seen in patients with schizophrenia. Evidence obtained from human post-mortem samples have shown decreased levels of D-Asp in the prefrontal cortex and striatum of patients with schizophrenia compared to non-psychiatric controls.¹⁵²This decrease is associated with enhanced D-Asp catabolism by DDO.¹⁵³ Because D-Asp levels peak in the embryonic phase and undergo strict developmental regulation, such decreased D-Asp in the brain could be associated with disorders that occurred early in development, as proposed by the neurodevelopmental hypothesis of schizophrenia.¹⁵⁴ DDO is also regarded as a potential therapeutic target for schizophrenia, and multiple compounds that inhibit DDO activity have been identified in vitro¹⁵⁵ and in silico.¹⁵⁶

3.3. D-Amino acids from commensal and pathogenic bacteria in mammals

Given the diverse capacities of bacteria to metabolize D-amino acids, the presence of D-amino acids of bacterial origin in mammals has long been assumed. In the mid 1960s, Hoeprich was the first to suggest that the gut microbiota was the source of serum D-Ala in rodents.¹⁵⁷ Using antibiotic-treated mice lacking DAO activity, Konno et al. showed that the majority of D-Ala excreted in the urine is of intestinal bacterial origin.¹⁵⁸ This finding was further confirmed using germ-free (GF) animals.¹⁵⁹ Serum D-Ala levels in GF mice are significantly lower than those in mice raised in specific-pathogen free (SPF) conditions.¹⁶⁰ This finding proved the presence of bacterial D-Ala in the circulation, although its uptake mechanism in the intestine is not known. Intriguingly, D-Ala levels in rodents are highest in the anterior pituitary gland and second highest in the pancreas. Moreover, D-Ala levels follow a food-intake independent circadian rhythm, which is not found in the levels of L-Ala, D/L-Ser, or D/L-Asp.^160,161,162 In rats, D-Ala is distributed in adrenocorticotropic hormone-secreting cells in the pituitary gland and in insulin producing beta-cells in the pancreas.^163,164 Such a distribution implies the involvement of D-Ala in hormonal regulation. Indeed, D-Ala stored in the islets of rat pancreas is released in response to extracellular glucose.¹⁶⁵

In addition to the potential role of bacterial D-Ala in the mammalian endocrine system, growing evidence supports the view that recognition of D-amino acids in mammals can be associated with discrimination between self and nonself in the immune system. Because DAO, conserved widely in eukaryotes but not in bacteria,¹⁶⁶ is able to generate hydrogen peroxide through catabolism of D-amino acids, DAO has been considered a potential component of the innate host defense. In 1969, Cline and Lehrer first identified DAO activity in the granule fraction of human neutrophilic leukocytes;¹⁶⁷ this DAO activity is linked to bactericidal activity of leukocytes by H₂O₂.^168,169 A later study showed that DAO is localized in the neutrophilic surface, internalized during phagocytosis, and is capable of H₂O₂ production within the phagosome.¹⁷⁰ Mice lacking DAO activity were shown to be more susceptible to intravenous injection with Staphylococcus aureus,¹⁷¹ supporting a role for neutrophilic DAO in systemic innate defense that is responsive to microbial input. More recently, microbial D-amino acids also have been associated with the immune system in the mucosa.^172,173,174 DAO activity has been reported in the small intestine luminal epithelium of fish,¹⁷⁵ chicken,¹⁷⁶ mice, and humans.¹⁷² Intestinal DAO found in goblet cells is secreted into the lumen and modifies the composition of the commensal microbiota and protects the mucosal surface from the cholera pathogen in mice.¹⁷² Of note, the gut microbiota produces the vast majority of intestinal D-amino acids, including D-Ala, D-Asp, D-Glu, and D-Pro, and induces expression of DAO limited to the intestine¹⁷² (Fig. 4). These findings support the homeostatic role of DAO-mediated D-amino acid metabolism in the host–microbe interface.

Fig. 4

. Standard bacterial D-amino acids detected in the intestine. D-Ala, D-Asp, D-Glu, and D-Pro of bacterial origin are typically detected in the luminal content of the small intestine. In addition to these four D-amino acids, D-Arg and D-Lys are also detected in the colon. The levels of D-amino acids are much higher in the colon than in the small intestine because their levels are mostly determined by the number of regional bacteria.

In the upper respiratory airway, commensal Staphylococcus species inhibit biofilm formation by Pseudomonas aeruginosa through production of at least two D-amino acids (D-Leu and D-Phe) that activate the sweet taste receptors (T1R2/3) in solitary chemosensory cells involved in antimicrobial innate defense.¹⁷⁴ Furthermore, such activation of T1R2/3 by the D-amino acids inhibits signaling from bitter taste receptors (T2Rs) and, in turn, secretion of beta-defensin1,¹⁷⁴ an antimicrobial peptide implicated in the resistance to microbial colonization. Moreover, the influence of a microbial D-amino acid in acquired immunity has been reported by Kepert et al. They identified that D-Trp, screened from the supernatants of probiotic bacteria, reduced Th2-activity associated chemokine ligand 17 (CCL17) secretion in a human Hodgkin lymphoma T-cell line. D-Trp also has biological activity in human monocyte-derived dendritic cells where it strongly induces IL-10 and decreases LPS-induced IFN-gamma, IL-12, and IL-5. Oral supplementation of D-Trp in mice alters the diversity of the gut microbiota, increases the numbers of lung and colon Treg cells, decreases lung Th2 responses, and ameliorates allergic airway inflammation and hyperresponsiveness.¹⁷³ Although further mechanisms underlying the connection between innate and acquired immunity modified by microbial D-amino acids remain largely unknown, recognition of microbial D-amino acids by mammalian enzymes or receptors may play a significant role in systemic and mucosal innate/acquired immunity.

3.4. D-Amino acids in peptide or protein in humans

Over recent decades, non-enzymatic modification of protein-bound L-Asp to D-Asp and L-Ser to D-Ser has been described in “long-lived” proteins from various tissues in humans.^34,177 Among the amino acid residues in proteins, Asp residues are most frequently inverted from the L- to D-configuration if the neighboring amino-acid residue has a small side chain, e.g., Gly, Ala, or Ser, because Asp-specific stereoinversion occurs readily via succinimide intermediates.¹⁷⁸ Indeed, D-Asp residues have been detected in diverse proteins (e.g., elastin, crystallins, myelin, osteocalcin, phosphophoryn, beta-amyloid, and alpha-synuclein) from multiple metabolically inert tissues of elderly individuals such as artery, eye lens, cartilage, dentine, and brain. D-Ser residues have also been reported in beta-amyloid protein in the brain,¹⁷⁹ and in alpha-crystallin in the eye lens¹⁸⁰ from aged individuals. Such D-amino acid residues in “long-lived” proteins arise non-enzymatically in an age-dependent manner¹⁸¹ and are detected in age-dependent diseases such as neurodegenerative diseases,^182,183,184 cataract,¹⁸⁵ and atherosclerosis,¹⁸⁶ suggesting that this type of protein denaturation is linked to protein aggregation-related diseases. Recently, two D-Asp-containing peptides, both of which derive from the glycoprotein fibrinogen B, were identified in human serum.¹⁸⁷ Because 80% of fibrinogen circulates in the blood with a half-life of about 4 days and is not a “long-lived” protein, it remains uncertain whether such D-Asp residues are introduced via the conventional mechanism involving succinimide intermediates. To the best of our knowledge, it is not known whether NRP pathways exist that can incorporate D-amino acids or whether post-translational modification of racemization occurs in the peptides or proteins in humans. Interestingly, venom in the platypus, an Australian mammal, is known to contain an isomerase that reversibly stereoconverts the second amino-acid residue in some peptides between L- and D-forms.¹⁸⁸ Such post-translational modification might exist also in humans to provide functional diversity of protein.

3.5. Systemic regulation of D-amino acids in mammals: a potential marker for kidney disease

D-Amino acids in plasma originate from dietary uptake, microbial metabolism, and tissues that express amino acid racemases. As stated above, tissue-originated intrinsic D-amino acids are presumably restricted to D-Ser and D-Asp, whereas microbial D-amino acids include D-Ala, D-Glu, D-Pro, D-Asp, and other non-canonical D-amino acids. Bacteria-fermented foodstuffs (cheese, yogurt, sourdough, and pickles), beverages (wine, beer, and vinegar), and seafood such as bivalves and crustaceans contain substantial amounts of single or multiple types of D-amino acids, including D-Ala, D-Asp, D-Glu, and D-Pro.¹⁸⁹ Although the overall variety and amounts of D-amino acids absorbed daily in the intestine remain uncertain, most D-amino acids taken up in the intestine are degraded by DAO and DDO expressed in the epithelium of intestine and kidney. The degradation products are alpha-keto acids that are utilized for energy metabolism, or a part of D-amino acids are directly excreted in the urine. Most plasma D-amino acid levels are below 1% of that of their L-enantiomers.^104,190 However, urinary amino acids contain significant proportions of D-enantiomers: 40–60% of Ser; 20% of Ala, Asp, and Arg; 8–10% of Asp; and 6% of Met.^87,127 Physiological levels of plasma D-amino acids are finely regulated and are maintained at a low level with little individual variability in mammals, including humans.^88,191,192 The concentration of D-amino acids in urine strongly implies the presence of an enantioselective regulation mechanism in the kidney. The kidney plays a major role in the homeostasis of body amino acid pools. Given that D-amino acids as well as L-amino acids are constantly filtered in the renal glomeruli, reabsorption in the proximal tubules can be involved in the enantioselective regulation of plasma and urinary amino acids. Chiral selectivity of amino acid transport in the kidney is not well understood, except for some evidence on D-Ser transport. There are two proposed mechanisms that maintain L-Ser dominance on the basolateral side and the concentration of D-Ser on the luminal side of renal tubules in the kidney: L-Ser preferential reabsorption in the proximal convoluted tubule but not in pars recta^193,194,195, and intracellular degradation of D-Ser by tubular DAO.^{88,196,197,198} Because both mechanisms take place in the proximal tubule, renal pathology that involves proximal tubules is thought to perturb the homeostasis of serine enantiomers in the body fluid. Plasma D-Ser levels in patients with advanced renal failure can be higher than 20% of total Ser, whereas D-Ser levels in controls account for ~3% of total Ser.^199,200,201 Renal ischemic reperfusion injury in mice results in increased levels of serum D-Ser over time in proportion to the increase of serum creatinine. In contrast, such injury sharply reduces the urinary D-/L-Ser ratio in the very early phase prior to alterations of other renal markers such as serum creatinine, urinary kidney injury molecule-1, or urinary neutrophil gelatinase-associated lipocalin.²⁰² A longitudinal cohort study of plasma D-amino acids in 108 patients with chronic kidney disease found that the levels of D-Ser, D-Pro, and D-Asn are strongly associated with kidney function, and that D-Ser and D-Asn levels are associated with progression of the disease.¹⁹² Therefore, D-amino acids in the body fluid could be a promising early detection marker or a prognostic marker for kidney disease. Further investigation of the mechanisms explaining why some plasma D-amino acid concentrations correlate well with kidney function and how D-amino acids are regulated by renal transporters is warranted.

Final Remarks

We have presented an overview of the biological roles of free D-amino acids as well as protein-bound D-amino acids in bacteria, archaea, and eukaryotes, with particular focus on mammals. In the past few decades, technological advances, including the chiral separation of amino acids, have unveiled the crucial roles of intrinsic D-amino acids, especially in mammalian neurobiology. Considering the extensive influence of the microbiota on human physiology and pathology, recent progress in understanding the roles of microbial D-amino acids in mammals warrants further studies. Such studies should focus on the immune system, endocrine system, energy metabolism, and gut–brain signaling.

Acknowledgements

We thank M. Yasui and S. Aiso for indispensable support. J.S. is funded by JSPS KAKENHI Grant Number 16K09327, The Moritani Scholarship Foundation, and The Keio Gijuku Fukuzawa Memorial Fund for the Advancement of Education and Research. M.S. is supported by a Grant-in-Aid for JSPS Research Fellow (Grant Number 17J10213).

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