Structural basis of d-DOPA oxidation by d-amino acid oxidase: Alternative pathway for dopamine biosynthesis

Kawazoe, Tomoya; Tsuge, Hideaki; Imagawa, Takahito; Aki, Kenji; Kuramitsu, Seiki; Fukui, Kiyoshi

doi:10.1016/j.bbrc.2007.01.181

Cited by 62 publications

(79 citation statements)

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“…Specifically, our aim was to generate azide-or alkyne-bearing derivatives of the imino-DOPA ligand molecule. As mentioned previously, the binding mode of imino-DOPA with hDAO has been significantly clarified by X-ray co-crystal analysis [35][36][37] (Fig. 2A).…”

Section: Resultssupporting

confidence: 57%

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<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Toguchi

Hirose

Yorita

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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In situ click chemistry is a target-guided synthesis approach for discovering novel lead compounds by assembling organic azides and alkynes into triazoles inside the affinity site of target biogenic molecules such as proteins. We report in situ click chemistry screening with human D-amino acid oxidase (hDAO), which led to the identification of a more potent hDAO inhibitor. The hDAO inhibitors have chemotherapeutic potential as antipsychotic agents. The new inhibitor displayed competitive inhibition of hDAO and showed significantly increased inhibitory activity against hDAO compared with that of an anchor molecule of in situ click chemistry.Key words fragment-based lead discovery; templated reaction; ligand-binding site; drug discovery; triazole formation; ligand affinity Although D-amino acids exist in a wide range of organisms, they are nonetheless often called unnatural amino acids. D-Serine is abundant in the forebrain and acts as an endogenous co-agonist of N-methyl-D-aspartate (NMDA) receptors to enhance neurotransmission. 1) D-Amino acid oxidase (DAO) was the first flavoenzyme to be identified, in 1935 by Krebs,2) and catalyzes the oxidative deamination reaction of D-amino acids. This reaction by human DAO (hDAO) in the brain primarily converts D-serine to hydroxypyruvate to regulate the concentration of D-serine. The overexpression of hDAO in the brain therefore causes neuropsychiatric disorders such as schizophrenia, a serious public health problem that affects nearly 0.8% of the global population, by reducing the amount of D-serine below the level required for adequate neuronal function.3,4) Furthermore, a protein from the human gene G72 has been identified as an interacting partner to activate hDAO, and the association of both DAO and gene G72 with schizophrenia together with activation of hDAO activity by a G72 protein product points to the involvement of the regulation of NMDA receptor. 5) Thus, hDAO inhibitors have potential to be lead compounds to the development of therapeutic agents for schizophrenia.Within the realm of click chemistry research, triazole formation between organic azide and alkyne is widely recognized. Triazole formation includes the 1,3-dipolar reaction known as the Huisgen cycloaddition, [6][7][8][9] and catalytic reactions that selectively afford the corresponding 1,4-substituted triazole or 1,5-substituted triazole using monovalent copper 10,11) or ruthenium reagents, 12,13) respectively. In situ click chemistry is a target-guided synthesis (TGS) method for the fast and efficient production of potential inhibitors against target biomolecules such as enzymes. Using this approach, complementary alkyne and azide building are assembled at binding sites and then accelerate the Huisgen 1,3-dipolar cycloaddition reaction to afford the corresponding conventional triazole, as illustrated in Fig. 1.To date, in situ click chemistry research has garnered success in inhibitor explorations where acetylcholinester-

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Section: Resultssupporting

confidence: 57%

“…[31][32][33][34][35] Of these structures, the complex of imino-3,4-dihydroxyphenylalanine (DOPA) bound to hDAO provides the best option for the design of an anchor molecule for using in situ click chemistry screening. Specifically, our aim was to generate azide-or alkyne-bearing derivatives of the imino-DOPA ligand molecule.…”

Section: Resultsmentioning

confidence: 99%

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

Toguchi

Hirose

Yorita

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…S1 in the supplemental material). Such inhibition was also observed in hDAO by D-tyrosine, D-phenylanaline, and D-DOPA (35). The inhibitory mechanism has not yet been determined but is suggested to be such that a second substrate binds to the active site in an orientation that makes the progression of the reaction unlikely.…”

Section: Discussionmentioning

confidence: 91%

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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“…To facilitate comparison of the structures, in all four examples the helix was positioned horizontally with the b-strands below it. Example proteins are D-amino acid oxidase [12], glutathione reductase [13], phosphoglycerate dehydrogenase [14], and lactate dehydrogenase [15]. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.…”

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confidence: 99%

Proteopedia: Rossmann fold: A beta‐alpha‐beta fold at dinucleotide binding sites

Hanukoglu

2015

Biochem Molecular Bio Educ

113

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The Rossmann fold is one of the most common and widely distributed super-secondary structures. It is composed of a series of alternating beta strand (b) and alpha helical (a) segments wherein the b-strands are hydrogen bonded forming a b-sheet. The initial beta-alpha-beta (bab) fold is the most conserved segment of Rossmann folds. As this segment is in contact with the ADP portion of dinucleotides such as FAD, NAD, and NADP it is also called as an "ADPbinding bab fold". The Proteopedia entry on the Rossmann fold (Available at: http://proteopedia.org/w/Rossmann_fold) was generated to illustrate several structural aspects of super families of FAD and NAD(P) binding proteins: (1) The coenzymes FAD and NAD(P) share the basic adenosine diphosphate (ADP) structure. (2) The bab fold motif that is common to both FAD and NAD(P) binding enzymes accommodates the common ADP component of these two coenzymes. (3) In both FAD and NAD(P) binding sites, the tight turn between the first b-strand and the a-helix is in contact with the two phosphate groups of ADP. (4) Keywords: protein structure function and folding; enzymes and catalysis; protein design; biochemical evolution; molecular graphics and representations; comparative biochemistryIn a very large superfamily of dinucleotide binding enzymes, the domains that bind a dinucleotide such as FAD, NAD, and NADP share a common super-secondary structure that is partly composed of a series of alternating beta strand (b) and alpha helical (a) segments wherein the b-strands are hydrogen bonded forming a central b-sheet with helices on either side. There can be up seven strands in one sheet. This domain structure was named "Rossmann fold" after Michael G. Rossmann who first reported it as a common structure in a variety of nucleotide binding proteins, such as lactate dehydrogenase and flavodoxin [1].The Rossmann fold is one of the five most common structural motifs that appear in a myriad of proteins [2,3]. The most widely distributed protein folding motifs are thought to be remnants of most ancient protein architectures [2,3]. In many textbooks, the Rossmann fold is defined as a babab structure in accordance with the original report [1]. However, elucidation of the structures of many dinucleotide binding enzymes revealed a great diversity in the overall structure of the dinucleotide binding domains. The major differences among dinucleotide binding domains of proteins include extensive divergence of the primary structure, variable number of b-strands in the complete b-sheet that forms the Rossmann fold, and large variations in the length and secondary structure of the segment that connects the second and third b-strands.The diversity of the Rossmann fold can be illustrated by two enzymes as examples. In dogfish lactate dehydrogenase the NAD binding motif, babab fold, is a continuous 60 residues long segment (PDB ID: 3LDH) [4]. In contrast, in yeast D-amino acid oxidase, the FAD binding domain includes only the initial bab fold in a continuous segment of 30 residues, but betwee...

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Structural basis of d-DOPA oxidation by d-amino acid oxidase: Alternative pathway for dopamine biosynthesis

Cited by 62 publications

References 30 publications

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

<i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor

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

Proteopedia: Rossmann fold: A beta‐alpha‐beta fold at dinucleotide binding sites

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