Is rat an appropriate animal model to study the involvement of <scp>d</scp>‐serine catabolism in schizophrenia? insights from characterization of <scp>d</scp>‐amino acid oxidase

Frattini, Luca; Piubelli, Luciano; Sacchi, Silvia; Molla, Gianluca; Pollegioni, Loredano

doi:10.1111/j.1742-4658.2011.08354.x

Cited by 27 publications

(38 citation statements)

References 40 publications

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“…Thus, elucidating the underlying mechanism of rDAAO accumulation will provide a better understanding of species-specific findings during non-clinical drug safety testing and will therefore result in an improved human health risk assessment. Indeed, since DAAO has been a pharmacological target , the suggested differences in propiverineinduced accumulation between rats and humans also raise questions regarding the appropriateness of rats as a model system for testing new drugs for the treatment of schizophrenia and neuropathic pain (Frattini et al 2011).…”

Section: Discussionmentioning

confidence: 99%

“…Recombinant rDAAO and hDAAO were expressed in BL21(DE3)Star E. coli strain and purified as previously reported in (Frattini et al 2011) and (Molla et al 2006), respectively.…”

Section: Recombinant Proteinsmentioning

confidence: 99%

“…Thus, we first evaluated the ability of propiverine or propiverine-N-oxide to interact with recombinant rat DAAO (rDAAO). We performed spectral analyses using the recombinant rat and human (hDAAO) proteins, since it is well documented that the binding of ligands in the active site of the flavoenzyme yields to concentration-dependent perturbations of the visible absorbance spectrum (Harris et al 1999;Molla et al 2006;Frattini et al 2011). Notably, only minimal changes in the spectrum were observed following the titration with both propiverine and propiverine-N-oxide, suggesting that neither of the two compounds is an rDAAO ligand (Fig.…”

Section: Recombinant Daao Properties Are Unaffected By Propiverinementioning

confidence: 99%

“…Mammalian DAAO is expressed in kidney, liver and brain (descending order of expression level), whereby mice represent an exception as no hepatic expression was detected (Pollegioni et al 2007;Konno et al 2009). Rat DAAO (rDAAO) shares 93 and 80 % sequence identity with mouse DAAO (mDAAO) and human (hDAAO), respectively (Konno 1998); nonetheless, rDAAO differs significantly from the human counterpart regarding structural, biochemical and kinetic properties: (1) rDAAO consists of 346 amino (38.8 kDa), whereas hDAAO consists of 347 amino acid residues (39.5 kDa) (Konno 1998), (2) rDAAO is a monomer in the concentration range 1-20 mg/mL (Frattini et al 2011) while hDAAO is a stable dimer (Molla et al 2006), (3) rDAAO shows lower kinetic efficiency and a different substrate specificity as compared to the human counterpart (Frattini et al 2011), and, most importantly, (4) rDAAO and hDAAO differ in affinity for the binding of classical inhibitors (Molla et al 2006;Caldinelli et al 2010;Frattini et al 2011).…”

Section: Introductionmentioning

confidence: 99%

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Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

et al. 2016

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Section: Discussionmentioning

confidence: 99%

“…Recombinant rDAAO and hDAAO were expressed in BL21(DE3)Star E. coli strain and purified as previously reported in (Frattini et al 2011) and (Molla et al 2006), respectively.…”

Section: Recombinant Proteinsmentioning

confidence: 99%

Section: Recombinant Daao Properties Are Unaffected By Propiverinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

et al. 2016

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“…DAOs of rat (rDAO) and the yeast Candida boidinii (CbDAO) are also monomers, but the former enzyme forms a dimer in the presence of an inhibitor (29,30). In addition, the oligomerization state of pkDAO is dependent on protein concentration (2).…”

Section: Discussionmentioning

confidence: 99%

A Highly Stable d -Amino Acid Oxidase of the Thermophilic Bacterium Rubrobacter xylanophilus

Takahashi

Furukawara

Omae

et al. 2014

Appl Environ Microbiol

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D-Amino acid oxidase (DAO) is a biotechnologically attractive enzyme that can be used in a variety of applications, but its utility is limited by its relatively poor stability. A search of a bacterial genome database revealed a gene encoding a protein homologous to DAO in the thermophilic bacterium Rubrobacter xylanophilus (RxDAO). The recombinant protein expressed in Escherichia coli was a monomeric protein containing noncovalently bound flavin adenine dinucleotide as a cofactor. This protein exhibited oxidase activity against neutral and basic D-amino acids and was significantly inhibited by a DAO inhibitor, benzoate, but not by any of the tested D-aspartate oxidase (DDO) inhibitors, thus indicating that the protein is DAO. RxDAO exhibited higher activities and affinities toward branched-chain D-amino acids, with the highest specific activity toward D-valine and catalytic efficiency (k cat /K m ) toward D-leucine. Substrate inhibition was observed in the case of D-tyrosine. The enzyme had an optimum pH range and temperature of pH 7.5 to 10 and 65°C, respectively, and was stable between pH 5.0 and pH 8.0, with a T 50 (the temperature at which 50% of the initial enzymatic activity is lost) of 64°C. No loss of enzyme activity was observed after a 1-week incubation period at 30°C. This enzyme was markedly inactivated by phenylmethylsulfonyl fluoride but not by thiol-modifying reagents and diethyl pyrocarbonate, which are known to inhibit certain DAOs. These results demonstrated that RxDAO is a highly stable DAO and suggested that this enzyme may be valuable for practical applications, such as the determination and quantification of branched-chain D-amino acids, and as a scaffold to generate a novel DAO via protein engineering.T he flavoenzyme D-amino acid oxidase (DAO; EC 1.4.3.3) catalyzes the oxidative deamination of neutral and basic D-amino acids but not of acidic D-amino acids, which are substrates of D-aspartate oxidase (DDO). DAO was first identified in pig kidney (pkDAO) by Krebs in 1935 (1) and subsequently has been found mainly in eukaryotic organisms, ranging from fungi to humans (2). These eukaryotic DAOs have been extensively studied as a model of the oxidase-dehydrogenase class of flavoproteins. In fungi, the enzyme plays a role in the assimilation of D-amino acids for cell growth and also in the detoxification of D-amino acid toxicity (2, 3). In vertebrates, this enzyme is mainly localized in the liver and kidney, and it metabolizes both exogenous and endogenous D-amino acids (2). In addition, the enzyme plays a specific role in the regulation of D-serine, a coagonist for the N-methyl-Daspartate receptor, in the brain (2).In contrast, for a long time, it was thought that DAO did not exist in prokaryotic organisms. However, this enzyme was recently identified in Arthrobacter protophormiae (ApDAO) and Streptomyces coelicolor (ScDAO) (4, 5). In addition to these bacterial species, a search of a prokaryotic genome database revealed a wide distribution of DAO homologous proteins in bacteria, especially a...

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Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

et al. 2017

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Proper subcellular trafficking is essential to prevent protein mislocalization and aggregation. Transport of the peroxisomal enzyme D-amino acid oxidase (DAAO) appears dysregulated by specific pharmaceuticals, e.g., the anti-overactive bladder drug propiverine or a norepinephrine/serotonin reuptake inhibitor (NSRI), resulting in massive cytosolic and nuclear accumulations in rat kidney. To assess the underlying molecular mechanism of the latter, we aimed to characterize the nature of peroxisomal and cyto-nuclear shuttling of human and rat DAAO overexpressed in three cell lines using confocal microscopy. Indeed, interference with peroxisomal transport via deletion of the PTS1 signal or PEX5 knockdown resulted in induced nuclear DAAO localization. Having demonstrated the absence of active nuclear import and employing variably sized mCherry- and/or EYFP-fusion proteins of DAAO and catalase, we showed that peroxisomal proteins ≤134 kDa can passively diffuse into mammalian cell nuclei-thereby contradicting the often-cited 40 kDa diffusion limit. Moreover, their inherent nuclear presence and nuclear accumulation subsequent to proteasome inhibition or abrogated peroxisomal transport suggests that nuclear localization is a characteristic in the lifecycle of peroxisomal proteins. Based on this molecular trafficking analysis, we suggest that pharmaceuticals like propiverine or an NSRI may interfere with peroxisomal protein targeting and import, consequently resulting in massive nuclear protein accumulation in vivo.

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Is rat an appropriate animal model to study the involvement of d‐serine catabolism in schizophrenia? insights from characterization of d‐amino acid oxidase

Cited by 27 publications

References 40 publications

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

Novel insights into renal d-amino acid oxidase accumulation: propiverine changes DAAO localization and peroxisomal size in vivo

A Highly Stable d -Amino Acid Oxidase of the Thermophilic Bacterium Rubrobacter xylanophilus

Understanding renal nuclear protein accumulation: an in vitro approach to explain an in vivo phenomenon

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