Biochemical characterization of mouse d-aspartate oxidase

Puggioni, Vincenzo; Savinelli, Antonio; Miceli, Matteo; Molla, Gianluca; Pollegioni, Loredano; Sacchi, Silvia

doi:10.1016/j.bbapap.2020.140472

Cited by 5 publications

(10 citation statements)

References 54 publications

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“…The melting temperature determined following the loss of activity is 55°C (Katane et al, 2015a), higher than the value obtained following the CD signal at 222 nm (48.8°C) (Molla et al, 2020), this suggesting that the alteration in secondary structure leads to the loss of enzymatic activity. Both human and mouse DASPOs are stabilized by the presence of ligands in the active site (Molla et al, 2020;Puggioni et al, 2020). As the bovine counterpart, the holoenzyme form of recombinant hDASPO is a monomer with a molecular mass of ∼40 kDa.…”

Section: Biochemical Propertiesmentioning

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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Section: Biochemical Propertiesmentioning

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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“…Once produced, D-aspartate can act on its own, be metabolized to NMDA, or degraded by DDO [ 102 ]. This pathway is still being actively studied, and indeed a recent study detailing mouse DDO has shown some significant differences between mouse and human DDO [ 35 ]. In particular, mouse DDO showed increased cross reactivity with D-proline, and decreased flavin adenine dinucleotide binding compared to its human counterpart [ 35 ].…”

Section: Nmda Receptor Agonists or Co-agonistsmentioning

confidence: 99%

“…Neurologically active D-amino acids are tightly regulated within the brain by the D-amino acid oxidase (DAAO) and D-aspartate oxidase (DDO) [ 1 , 35 ]. These two oxidases catalyze the oxidative deamination of their respective substrates and allow them to be excreted by the kidneys [ 35 , 42 ]. Most importantly D-Serine and D-Alanine are metabolized by human DAAO, while D-aspartate and D-glutamate are metabolized by DDO [ 42 , 92 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is likely that all D-amino acids not metabolized by either DAAO or DDO and are simply excreted by the kidneys as their primary method of elimination in humans. As most of the active D-amino acids are thought to be regulated by a single enzyme, there has been a plethora of recent studies on DAAO activity and its effects on D-amino acids levels within the body [ 30 , 35 , 36 , 40 , 52 , 68 , 80 , 96 ]. These studies will be discussed in detail in the following sections.…”

Section: Introductionmentioning

confidence: 99%

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Advances in D-Amino Acids in Neurological Research

Seckler

Lewis

2020

IJMS

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D-amino acids have been known to exist in the human brain for nearly 40 years, and they continue to be a field of active study to today. This review article aims to give a concise overview of the recent advances in D-amino acid research as they relate to the brain and neurological disorders. This work has largely been focused on modulation of the N-methyl-D-aspartate (NMDA) receptor and its relationship to Alzheimer’s disease and Schizophrenia, but there has been a wealth of novel research which has elucidated a novel role for several D-amino acids in altering brain chemistry in a neuroprotective manner. D-amino acids which have no currently known activity in the brain but which have active derivatives will also be reviewed.

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“…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 Nementioning

confidence: 99%

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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Biochemical characterization of mouse d-aspartate oxidase

Cited by 5 publications

References 54 publications

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

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

Advances in D-Amino Acids in Neurological Research

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

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