d-Aspartate oxidase: distribution, functions, properties, and biotechnological applications

Takahashi, Shouji

doi:10.1007/s00253-020-10439-9

Cited by 15 publications

(13 citation statements)

References 96 publications

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“…This atypical amino acid has been found in the CNS of rats [20,21], mice [22][23][24], and humans [10,13,25]. Although amino acids are predominantly present in mammalian tissues in the L-form, D-Asp content in the human embryonic prefrontal cortex (PFC) exceeds even the amount of its enantiomer, L-Asp (mean values: D-Asp = 0.036 µmol/g, L-Asp = 0.21 µmol/g), while the levels of this D-amino acid are drastically reduced at adulthood (0.008 µmol/g) [9,10,25,26]. In line with this finding, immunohistochemical studies in the rat embryonic brain revealed that D-Asp appears within the hindbrain at embryonic day (E) 12, and then in the mid and forebrain at E20.…”

Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

“…On the other hand, it has long been known that DDO is the degradative enzyme responsible for D-Asp catabolism [23,25]. In fact, DDO is a peroxisomal flavoprotein that catabolizes the oxidative deamination of D-Asp to generate α-oxaloacetate, hydrogen peroxide, and ammonia (for more recent insights on DDO biochemical properties and structure-functional relationship in different species, see the reviews [9,[38][39][40]). The intracellular localization of DDO in organelles like peroxisomes enables the cell to safely contain the hydrogen peroxide produced by the degradative reaction [41].…”

Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

“…Nervous and endocrine tissues appear to contain the enzymatic systems required to modulate D-Asp homeostasis because they can synthesize and degrade this amino acid. Endogenous D-Asp racemase activity contributes to the biosynthesis of D-Asp from L-Asp, while D-aspartate oxidase (DDO), a peroxisomal flavoprotein that specifically metabolizes D-Asp into oxaloacetate, NH 3 , and H 2 O 2 [5][6][7][8][9]. D-Asp has a different pattern of occurrence in mammalian tissues.…”

Section: Introductionmentioning

confidence: 99%

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New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

Usiello

Fiore

Rosa

et al. 2020

IJMS

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The endogenous amino acids serine and aspartate occur at high concentrations in free D-form in mammalian organs, including the central nervous system and endocrine glands. D-serine (D-Ser) is largely localized in the forebrain structures throughout pre and postnatal life. Pharmacologically, D-Ser plays a functional role by acting as an endogenous coagonist at N-methyl-D-aspartate receptors (NMDARs). Less is known about the role of free D-aspartate (D-Asp) in mammals. Notably, D-Asp has a specific temporal pattern of occurrence. In fact, free D-Asp is abundant during prenatal life and decreases greatly after birth in concomitance with the postnatal onset of D-Asp oxidase expression, which is the only enzyme known to control endogenous levels of this molecule. Conversely, in the endocrine system, D-Asp concentrations enhance after birth during its functional development, thereby suggesting an involvement of the amino acid in the regulation of hormone biosynthesis. The substantial binding affinity for the NMDAR glutamate site has led us to investigate the in vivo implications of D-Asp on NMDAR-mediated responses. Herein we review the physiological function of free D-Asp and of its metabolizing enzyme in regulating the functions of the brain and of the neuroendocrine system based on recent genetic and pharmacological human and animal studies.

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Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

Section: Free D-aspartate Distribution In the Mammalian Central Nervomentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

Usiello

Fiore

Rosa

et al. 2020

IJMS

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“…As little is known about the biosynthetic pathway, the only way to control D-Asp levels in the brain is to modulate its degradation. In mammalian tissues, three enzymes able to stereoselectively degrade d -amino acids have been identified, namely, d -amino acid oxidase (DAAO or DAO, EC 1.4.3.3), DASPO, and d -glutamate cyclase (EC 4.2.1.48) ( Pollegioni et al, 2007 ; Katane and Homma, 2010 ; Takahashi 2020 ), the latter metabolizing d -glutamate (D-Glu), but not D-Asp in mouse heart ( Ariyoshi et al, 2017 ; Tateishi et al, 2017 ). DAAO and DASPO, discovered by Krebs in 1935 ( Krebs 1935 ), are peroxisomal flavoproteins ( Usuda et al, 1986 ; van Veldhoven et al, 1991 ; Zaar 1996 ; Zaar et al, 2002 ) that catalyze the oxidative deamination of d -amino acids into the corresponding α -ketoacids and ammonia; the reduced FADH 2 cofactor is regenerated by dioxygen, yielding hydrogen peroxide ( Figure 2 ).…”

Section: Introductionmentioning

confidence: 99%

“…DAAO oxidizes several neutral and basic d -amino acids (including D-Ser): the human enzyme (hDAAO) shows peculiar properties such as low kinetic efficiency and weak flavin binding ( Molla et al, 2006 ; Caldinelli et al, 2009 ; Sacchi et al, 2012 ). In contrast, DASPO is highly specific for acidic d -amino acids only ( Katane et al, 2015a ; Molla et al, 2020 ; Takahashi 2020 ), which are not oxidized by DAAO; the human DASPO (hDASPO) shows a high turnover and tight cofactor binding. DAAO and DASPO share a high sequence identity; thus, it has been proposed that they derive from a common ancestor ( Negri et al, 1992 ; Takahashi et al, 2004 ), but seemingly evolved to fulfil different and specific physiological roles.…”

Section: Introductionmentioning

confidence: 99%

Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism

Pollegioni

Molla

Sacchi

et al. 2021

Front. Mol. Biosci.

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In recent years, the D-enantiomers of amino acids have been recognized as natural molecules present in all kingdoms, playing a variety of biological roles. In humans, d-serine and d-aspartate attracted attention for their presence in the central nervous system. Here, we focus on d-aspartate, which is involved in glutamatergic neurotransmission and the synthesis of various hormones. The biosynthesis of d-aspartate is still obscure, while its degradation is due to the peroxisomal flavin adenine dinucleotide (FAD)-containing enzyme d-aspartate oxidase. d-Aspartate emergence is strictly controlled: levels decrease in brain within the first days of life while increasing in endocrine glands postnatally and through adulthood. The human d-aspartate oxidase (hDASPO) belongs to the d-amino acid oxidase-like family: its tertiary structure closely resembles that of human d-amino acid oxidase (hDAAO), the enzyme that degrades neutral and basic d-amino acids. The structure-function relationships of the physiological isoform of hDASPO (named hDASPO_341) and the regulation of gene expression and distribution and properties of the longer isoform hDASPO_369 have all been recently elucidated. Beyond the substrate preference, hDASPO and hDAAO also differ in kinetic efficiency, FAD-binding affinity, pH profile, and oligomeric state. Such differences suggest that evolution diverged to create two different ways to modulate d-aspartate and d-serine levels in the human brain. Current knowledge about hDASPO is shedding light on the molecular mechanisms underlying the modulation of d-aspartate levels in human tissues and is pushing novel, targeted therapeutic strategies. Now, it has been proposed that dysfunction in NMDA receptor-mediated neurotransmission is caused by disrupted d-aspartate metabolism in the nervous system during the onset of various disorders (such as schizophrenia): the design of suitable hDASPO inhibitors aimed at increasing d-aspartate levels thus represents a novel and useful form of therapy.

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Development of an aminotransferase‐driven biocatalytic cascade for deracemization of d,l‐phosphinothricin

Liu

Deng

et al. 2023

Biotech & Bioengineering

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Abstract2‐oxo‐4‐[(hydroxy)(methyl)phosphinoyl]butyric acid (PPO) is the essential precursor keto acid for the asymmetric biosynthesis of herbicide l‐phosphinothricin (l‐PPT). Developing a biocatalytic cascade for PPO production with high efficiency and low cost is highly desired. Herein, a d‐amino acid aminotransferase from Bacillus sp. YM‐1 (Ym DAAT) with high activity (48.95 U/mg) and affinity (Km = 27.49 mM) toward d‐PPT was evaluated. To circumvent the inhibition of by‐product d‐glutamate (d‐Glu), an amino acceptor (α‐ketoglutarate) regeneration cascade was constructed as a recombinant Escherichia coli (E. coli D), by coupling Ym d‐AAT, d‐aspartate oxidase from Thermomyces dupontii (TdDDO) and catalase from Geobacillus sp. CHB1. Moreover, the regulation of the ribosome binding site was employed to overcome the limiting step of expression toxic protein TdDDO in E. coli BL21(DE3). The aminotransferase‐driven whole‐cell biocatalytic cascade (E. coli D) showed superior catalytic efficiency for the synthesis of PPO from d,l‐phosphinothricin (d,l‐PPT). It revealed the production of PPO exhibited high space–time yield (2.59 g L−1 h−1) with complete conversion of d‐PPT to PPO at high substrate concentration (600 mM d,l‐PPT) in 1.5 L reaction system. This study first provides the synthesis of PPO from d,l‐PPT employing an aminotransferase‐driven biocatalytic cascade.

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d-Aspartate oxidase: distribution, functions, properties, and biotechnological applications

Cited by 15 publications

References 96 publications

New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

New Evidence on the Role of D-Aspartate Metabolism in Regulating Brain and Endocrine System Physiology: From Preclinical Observations to Clinical Applications

Human D-aspartate Oxidase: A Key Player in D-aspartate Metabolism

Development of an aminotransferase‐driven biocatalytic cascade for deracemization of d,l‐phosphinothricin

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