Identification of Novel <scp>d</scp>-Aspartate Oxidase Inhibitors by <i>in Silico</i> Screening and Their Functional and Structural Characterization <i>in Vitro</i>

Katane, Masumi; Yamada, Shota; Kawaguchi, Go; Chinen, Mana; Matsumura, Maya; Ando, Takemi; Doi, Issei; Nakayama, Kazuki; Kaneko, Yuusuke; Matsuda, Satsuki; Saitoh, Yasuaki; Miyamoto, Tomofumi; Sekine, Masae; Yamaotsu, Noriyuki; Hirono, Shuichi; Homma, Hiroshi

doi:10.1021/acs.jmedchem.5b00871

Cited by 20 publications

(20 citation statements)

References 59 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, since DDO has intracellular localization and is active within peroxisomes13, future studies are needed to clarify whether and how olanzapine has direct access to DDO in vivo . Regardless of the precise mechanism responsible for DDO inhibition, the potential relevance of DDO as a pharmacological target in schizophrenia shown by this and previous finding18 prompts to the discovery of novel compounds with inhibitory activity for this enzyme, as recently reported by Homma and co-workers48. In agreement with its agonistic profile not only at NMDARs but also at mGlu5 receptors49, previous observations showed that increased levels of D-Asp in preclinical models are associated with improved memory679, enhanced structural and functional synaptic plasticity11 and greater connectivity in cortico-hippocampal regions16.…”

Section: Discussionsupporting

confidence: 53%

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

Sacchi

Novellis

Paolone

et al. 2017

Sci Rep

View full text Add to dashboard Cite

D-aspartate levels in the brain are regulated by the catabolic enzyme D-aspartate oxidase (DDO). D-aspartate activates NMDA receptors, and influences brain connectivity and behaviors relevant to schizophrenia in animal models. In addition, recent evidence reported a significant reduction of D-aspartate levels in the post-mortem brain of schizophrenia-affected patients, associated to higher DDO activity. In the present work, microdialysis experiments in freely moving mice revealed that exogenously administered D-aspartate efficiently cross the blood brain barrier and stimulates L-glutamate efflux in the prefrontal cortex (PFC). Consistently, D-aspartate was able to evoke L-glutamate release in a preparation of cortical synaptosomes through presynaptic stimulation of NMDA, mGlu5 and AMPA/kainate receptors. In support of a potential therapeutic relevance of D-aspartate metabolism in schizophrenia, in vitro enzymatic assays revealed that the second-generation antipsychotic olanzapine, differently to clozapine, chlorpromazine, haloperidol, bupropion, fluoxetine and amitriptyline, inhibits the human DDO activity. In line with in vitro evidence, chronic systemic administration of olanzapine induces a significant extracellular release of D-aspartate and L-glutamate in the PFC of freely moving mice, which is suppressed in Ddo knockout animals. These results suggest that the second-generation antipsychotic olanzapine, through the inhibition of DDO activity, increases L-glutamate release in the PFC of treated mice.

show abstract

Section: Discussionsupporting

confidence: 53%

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

Sacchi

Novellis

Paolone

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Therefore, in the light of the dysfunctional DDO activity found in the DLPFC of SCZ patients, future studies will be mandatory to assess the occurrence of regulatory molecules and cellular factors that could tune the metabolic control played by DDO over d -Asp under physiological and pathologic conditions. In this regard, the recent pioneering research of novel inhibitors specific for hDDO 39 well suits with the idea to reduce the DDO activity in SCZ brain in the attempt to increase the availability of d -Asp and potentiate, in turn, the overall NMDAR-mediated transmission.…”

Section: Discussionmentioning

confidence: 98%

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients

et al. 2017

View full text Add to dashboard Cite

It is long acknowledged that the N-methyl d-aspartate receptor co-agonist, d-serine, plays a crucial role in several N-methyl d-aspartate receptor-mediated physiological and pathological processes, including schizophrenia. Besides d-serine, another free d-amino acid, d-aspartate, is involved in the activation of N-methyl d-aspartate receptors acting as an agonist of this receptor subclass, and is abundantly detected in the developing human brain. Based on the hypothesis of N-methyl d-aspartate receptor hypofunction in the pathophysiology of schizophrenia and considering the ability of d-aspartate and d-serine to stimulate N-methyl d-aspartate receptor-dependent transmission, in the present work we assessed the concentration of these two d-amino acids in the post-mortem dorsolateral prefrontal cortex and hippocampus of patients with schizophrenia and healthy subjects. Moreover, in this cohort of post-mortem brain samples we investigated the spatiotemporal variations of d-aspartate and d-serine. Consistent with previous work, we found that d-aspartate content was selectively decreased by around 30% in the dorsolateral prefrontal cortex, but not in the hippocampus, of schizophrenia-affected patients, compared to healthy subjects. Interestingly, such selective reduction was associated to greater (around 25%) cortical activity of the enzyme responsible for d-aspartate catabolism, d-aspartate oxidase. Conversely, no significant changes were found in the methylation state and transcription of DDO gene in patients with schizophrenia, compared to control individuals, as well as in the expression levels of serine racemase, the major enzyme responsible for d-serine biosynthesis, which also catalyzes aspartate racemization. These results reveal the potential involvement of altered d-aspartate metabolism in the dorsolateral prefrontal cortex as a factor contributing to dysfunctional N-methyl d-aspartate receptor-mediated transmission in schizophrenia.

show abstract

“…154 DDO is also regarded as a potential therapeutic target for schizophrenia, and multiple compounds that inhibit DDO activity have been identified in vitro 155 and in silico. 156…”

Section: Metabolic Disorder Of Intrinsic D-amino Acids: Psychiatric Amentioning

confidence: 99%

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

Sasabe

Suzuki

2018

Keio J. Med.

View full text Add to dashboard Cite

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.

show abstract

Identification of Novel d-Aspartate Oxidase Inhibitors by in Silico Screening and Their Functional and Structural Characterization in Vitro

Cited by 20 publications

References 59 publications

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

Olanzapine, but not clozapine, increases glutamate release in the prefrontal cortex of freely moving mice by inhibiting D-aspartate oxidase activity

Decreased free d-aspartate levels are linked to enhanced d-aspartate oxidase activity in the dorsolateral prefrontal cortex of schizophrenia patients

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

Contact Info

Product

Resources

About