d-Amino acid metabolism in mammals: Biosynthesis, degradation and analytical aspects of the metabolic study

Ohide, Hiroko; Miyoshi, Y.; Maruyama, Rindo; Hamase, Kenji; Konno, Ryuichi

doi:10.1016/j.jchromb.2011.06.028

Cited by 78 publications

(54 citation statements)

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“…Plasma levels of D-serine before D-serine treatment were 3.5 and 10.8 M in wild-type and DAAO-KO mice, respectively. Although genetic deletion of DAAO seems to result in increased plasma levels of D-serine, the origin of plasma D-serine is not well understood and could be attributed to diet (Friedman, 1999), the level formed in the brain by serine racemase (Ohide et al, 2011), or both. When D-serine was given to wild-type 129SvEv mice, D-serine was immediately absorbed and followed by rapid clearance.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice

et al. 2012

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“…In the cerebellum and spinal cord, the DAO activity is high Schell et al 1995), and the D-Ser amount is regulated to be low even in the mice having normal SRR activity (Nagata et al 1994;Miyoshi et al 2009). DAO is also expressed in the kidney (Ohide et al 2011) and choroid plexus (Ono et al 2009); the D-Ser in serum and CSF is considered to be regulated by DAO in these tissues. Therefore, the alterations of the D-Ser amounts in the cerebellum, spinal cord and physiological fluids following the change in SRR activity might not be drastic compared with those in the cerebral cortex and hippocampus.…”

Section: Discussionmentioning

confidence: 99%

“…As the enzymes relevant to D-Ser regulation in mammals, D-amino acid oxidase (DAO,EC 1.4.3.3) (Ohide et al 2011) and serine racemase (SRR, EC 5.1.1.18) (Wolosker et al 1999a, b) have been reported. DAO is an enzyme which catalyzes the oxidative deamination of neutral and basic D-amino acids including D-Ser (Neims et al 1966;D'Aniello et al 1993) and is predominantly localized in the kidney, liver and cerebellum (Ohide et al 2011).…”

Section: Introductionmentioning

confidence: 99%

“…DAO is an enzyme which catalyzes the oxidative deamination of neutral and basic D-amino acids including D-Ser (Neims et al 1966;D'Aniello et al 1993) and is predominantly localized in the kidney, liver and cerebellum (Ohide et al 2011). On the other hand, SRR is an enzyme synthesizing D-Ser from L-Ser and is highly expressed in the cerebral cortex and hippocampus (Wolosker et al 1999b;Miya et al 2008).…”

Section: Introductionmentioning

confidence: 99%

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Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase

et al. 2012

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For elucidation of the regulation mechanisms of intrinsic amounts of D-serine (D-Ser) which modulates the neuro-transmission of N-methyl-D-aspartate receptors in the brain, mutant animals lacking serine racemase (SRR) and D-amino acid oxidase (DAO) were established, and the amounts of D-Ser in the tissues and physiological fluids were determined. D-Ser amounts in the frontal brain areas were drastically decreased followed by reduced SRR activity. On the other hand, a moderate but significant decrease in D-Ser amounts was observed in the cerebellum and spinal cord of SRR knock-out (SRR(-/-)) mice compared with those of control mice, although the amounts of D-Ser in these tissues were low. The amounts of D-Ser in the brain and serum were not altered with aging. To clarify the uptake of exogenous D-Ser into the brain tissues, we have determined the D-Ser of SRR(-/-) mice after oral administration of D-Ser for the first time, and a drastic increase in D-Ser amounts in all the tested tissues was observed. Because both DAO and SRR are present in some brain areas, we have established the double mutant mice lacking SRR and DAO for the first time, and the contribution of both enzymes to the intrinsic D-Ser amounts was investigated. In the frontal brain, most of the intrinsic D-Ser was biosynthesized by SRR. On the other hand, half of the D-Ser present in the hindbrain was derived from the biosynthesis by SRR. These results indicate that the regulation of intrinsic D-Ser amounts is different depending on the tissues and provide useful information for the development of treatments for neuronal diseases.

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“…DAO and DDO are FAD-containing flavoproteins that catalyze the oxidative deamination of D-amino acids to generate 2-oxo acids along with hydrogen peroxide and ammonia. 22,23) DAO displays broad substrate specificity and acts on several neutral and basic D-amino acids, including 24,25) ; however, their physiological roles in vivo have yet to be clarified fully.…”

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confidence: 99%

Characterization of the Enzymatic and Structural Properties of Human D-Aspartate Oxidase and Comparison with Those of the Rat and Mouse Enzymes

Katane

Kawata

Nakayama

et al. 2015

Biological & Pharmaceutical Bulletin

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Human DDO is considered an attractive therapeutic target, and DDO inhibitors may be potential lead compounds for the development of new drugs against the aforementioned diseases. However, human DDO has not been characterized in detail and, although preclinical studies using experimental rodents are prerequisites for evaluating the in vivo effects of potential inhibitors, the existence of species-specific differences in the properties of human and rodent DDOs is still unclear. Here, the enzymatic activity and characteristics of purified recombinant human DDO were analyzed in detail. The kinetic and inhibitor-binding properties of this enzyme were also compared with those of purified recombinant rat and mouse DDOs. In addition, structural models of human, rat, and mouse DDOs were generated and compared. It was found that the differences among these DDO proteins occur in regions that appear involved in migration of the substrate/product in and out of the active site. In summary, detailed characterization of human DDO was performed and provides useful insights into the use of rats and mice as experimental models for evaluating the in vivo effects of DDO inhibitors. Alzheimer's disease, 9,10) and amyotrophic lateral sclerosis. Key words 11,12)Unlike the tissue-specific expression of D-Ser, substantial amounts of free D-Asp are present in a wide variety of mammalian tissues and cells, particularly those of the central nervous, neuroendocrine, and endocrine systems. Several lines of evidence suggest that D-Asp plays an important role in regulating developmental processes, hormone secretion, and steroidogenesis. [13][14][15] The amounts of D-Asp in human seminal plasma and spermatozoa are significantly lower in oligoasthenoteratospermic and azoospermic donors than normospermic donors. 16) Furthermore, in female patients undergoing in vitro fertilization, the D-Asp content of pre-ovulatory follicular fluid is lower in older patients than in younger patients; this decrease in D-Asp content appears to reflect a reduction in oocyte quality and fertilization competence. 17) Overall, current evidence suggests that decreases in D-Asp levels may be involved in the pathophysiology of infertility. Furthermore, D-Asp stimulates the NMDA receptor by acting as an agonist that binds to the L-Glu-binding site of the receptor. 18,19) Recent studies have suggested that, similar to D-Ser, D-Asp acts as a signaling molecule in nervous and neuroendocrine systems, at least in part, by binding to the NMDA receptor, and plays an important role in the regulation of brain functions. 14,15,20) In support of this proposal, it was reported recently that D-Asp levels in the prefrontal cortex and striatum of post-mortem brains of schizophrenic patients are significantly lower than those of non-psychiatrically ill individuals. 21) In mammalian tissues, two types of degradative enzymes that are stereospecific for D-amino acids have been identified, namely, D-amino acid oxidase (DAO, also abbreviated as DAAO; EC 1.4.3.3) and D-Asp oxidase (DDO, also ab...

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d-Amino acid metabolism in mammals: Biosynthesis, degradation and analytical aspects of the metabolic study

Cited by 78 publications

References 84 publications

Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice

Pharmacokinetics of Oral d-Serine in d-Amino Acid Oxidase Knockout Mice

Alteration of intrinsic amounts of d-serine in the mice lacking serine racemase and d-amino acid oxidase

Characterization of the Enzymatic and Structural Properties of Human D-Aspartate Oxidase and Comparison with Those of the Rat and Mouse Enzymes

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