The primary structure of the flavoprotein D-aspartate oxidase from beef kidney.

Negri, Armando; Ceciliani, Fabrizio; Tedeschi, Gioacchino; Simonic, Tatjana; Ronchi, Severino

doi:10.1016/s0021-9258(19)49778-0

Cited by 48 publications

(6 citation statements)

References 19 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Finally, analysis of the structure of DAAO active site (Mattevi et al, 1996;Todone et al, 1997) and the present experiments do not allow to explain the lack of interaction with D-aspartate or D-glutamate and the native or nicked DAAO forms. In this respect we found interesting the fact that there is a very low similarity between DAAO and D-aspartate oxidase in the loop region (Negri et al, 1992). Also the closely related DAAO from yeast exhibits little similarity with the pig kidney DAAO in the active site loop region (Faotto et al, 1995).…”

Section: Discussionmentioning

confidence: 79%

“…side chain, very poorly oxidizes amino acids with a positively charged side chain, and is inactive toward acidic amino acids (Dixon & Kleppe, 1965). D-Aspartate and D-glutamate are oxidatively deaminated by a specific D-aspartate oxidase (Negri et al, 1992). The kinetics of oxidation of amino acids catalyzed by DAAO differ according to the amino acid side chain (as reviewed in Curti et al, 1992).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,

et al. 1997

View full text Add to dashboard Cite

Limited proteolysis of D-amino acid oxidase holoenzyme with trypsin cleaves the protein at Arg 221 and near the C-terminus, producing stable 25, 13.4, and 2 kDa polypeptides [Torri-Tarelli, G., Vanoni, M. A., Negri, A., & Curti, B. (1990) J. Biol. Chem. 265, 21242-21246]. The 25 and 13.4 kDa polypeptides remain associated to form a nicked D-amino acid oxidase species. This nicked protein form maintains the ability to bind FAD, but exhibits altered catalytic efficiency toward the oxidation of various D-amino acids when compared to native DAAO. Changes in substrate specificity were first monitored by measuring the activity in the presence of different amino acid substrates at various times during proteolysis. Three amino acid substrates were then selected for further analysis of the properties of the nicked D-amino acid oxidase species produced by limited tryptic proteolysis: D-serine, D-arginine, and D-alanine. The three D-amino acids represented limiting cases of the observed changes of enzyme activity on nicking: loss of activity, increase of activity, and minor activity changes, respectively. D-serine was found to be no longer a substrate of D-amino acid oxidase. D-arginine exhibited a 2.5-fold increased apparent maximum velocity although its Km value increased 2-fold with the nicked enzyme in comparison to the native species. D-alanine was oxidized 1.5-fold faster by the nicked D-amino acid oxidase at infinite substrate concentration, and its Km value increased approximately 4-fold. The Kd for benzoate, which was determined kinetically with D-alanine as the enzyme substrate, increased 17-fold in the nicked species. Primary deuterium kinetic isotope effects on V and V/K during the oxidation of D-alanine were also measured. (D)V/K increased from 1.4 +/- 0.2 to 1.8 +/- 0.3 on nicking, while (D)V increased from 1.04 +/- 0.1 to 2.53 +/- 0.5. All the observed changes of the values of the kinetic parameters and of the observed isotope effects are consistent with the hypothesis that nicking of D-amino acid oxidase at position 221 decreases the strength of binding of both substrates and products to the enzyme active site. The information obtained by limited tryptic proteolysis nicely complements that gathered from the analysis of the three-dimensional structure of D-amino acid oxidase in complex with benzoate, which was recently determined [Mattevi, A., Vanoni, M. A., Todone, F., Rizzi, M., Teplyakov, A., Coda, A., Bolognesi, M., & Curti, B. (1996) Proc. Natl. Acad. Sci. U.S.A. 93, 7496-7501]. Arginine 221 is part of the 216-228 loop that covers the active site and contributes residues to substrate binding and catalysis. The limited proteolysis data support the hypothesis that this loop acts as a lid on the active site and controls both substrate specificity and the rate of turnover of D-amino acid oxidase.

show abstract

Section: Discussionmentioning

confidence: 79%

mentioning

confidence: 99%

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,

et al. 1997

View full text Add to dashboard Cite

show abstract

“…Unlike the situation with the GMC oxidoreductases, there is no other enzyme from the same family as d -amino acid oxidase which has seen comparable mechanistic study. d -Aspartate oxidase is homologous, with both the active site tyrosine and the active site arginine conserved, but there has been relatively little study of its mechanism to date. Monomeric sarcosine oxidase has the same fold as d -amino acid oxidase; however, the active site residues are not conserved between the two enzymes .…”

Section: Amino Acid Oxidationmentioning

confidence: 99%

Substrate Dehydrogenation by Flavoproteins

Fitzpatrick

2001

Acc. Chem. Res.

104

View full text Add to dashboard Cite

Enzymes with tightly bound FMN or FAD as cofactor catalyze the oxidation of a wide range of substrates. The chemical versatility of the isoalloxazine ring provides these enzymes with a range of potential mechanisms. Recent progress in elucidating the mechanisms of oxidation of organic substrates by flavoenzymes is described, focusing on the oxidation of alcohols, amino and hydroxy acids, amines, and nitroalkanes. With each family of enzymes, an attempt is made to integrate mechanistic, structural, and biomimetic data into a common catalytic mechanism.

show abstract

“…DASPO is a peroxisomal flavoenzyme primarily expressed in neuronal cells, encoded by the Ddo gene, and involved in the oxidative deamination of acidic D-amino acids, including D-aspartate and D-glutamate, with the following α-keto acid, ammonium, and hydrogen peroxide (H 2 O 2 ) production [ 24 , 268 , 269 ]. Even though DAO and DASPO may share a similar molecular structure and a common ancestral origin, the two enzymes diverge for several properties, showing different kinetic binding dynamics, flavin adenine dinucleotide (FAD) affinity, and substrate specificity, with a higher selectivity for neutral and basic or acidic D-amino acids, respectively [ 24 , 270 ]. In this regard, DASPO has shown a 10-fold higher specificity for D-aspartate compared with DAO specificity for D-serine [ 271 , 272 ].…”

Section: D-amino Acids As An Innovative Potential Therapeutic Approac...mentioning

confidence: 99%

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

et al. 2022

View full text Add to dashboard Cite

Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical–subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30–40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics’ effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.

show abstract

The primary structure of the flavoprotein D-aspartate oxidase from beef kidney.

Cited by 48 publications

References 19 publications

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,

Substrate Dehydrogenation by Flavoproteins

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

Contact Info

Product

Resources

About

The primary structure of the flavoprotein D-aspartate oxidase from beef kidney.

Cited by 48 publications

References 19 publications

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase,

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase,

Substrate Dehydrogenation by Flavoproteins

Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics

Contact Info

Product

Resources

About

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,

Limited Proteolysis and X-ray Crystallography Reveal the Origin of Substrate Specificity and of the Rate-Limiting Product Release during Oxidation of d-Amino Acids Catalyzed by Mammalian d-Amino Acid Oxidase^,