title: PEGylated D-serine dehydratase as a D-serine reducing agent.
abstract: D-Serine is an endogenous coagonist for N-methyl-D-aspartate (NMDA) receptors and is involved in excitatory neurotransmission. Excessive receptor activation causes excitotoxicity, leading to various acute and chronic neurological disorders. Decrease in D-serine content may provide a therapeutic strategy for the treatment of the neurological disorders in which overstimulation of NMDA receptors plays a pathological role. Saccharomyces cerevisiaed-serine dehydratase (Dsd1p), which acts dominantly on D-serine, may be a useful D-serine reducing agent. We conjugated a linear 5-kDa polyethylene glycol (PEG) to Dsd1p (PEG-Dsd1p) and examined the effects of PEG-conjugation on its biochemical and pharmacokinetic properties. PEG-Dsd1p retained activity, specificity, and stability of the enzyme. The PEG modification extended the serum half-life of Dsd1p in mice 6-fold, from 3.8h to 22.4h. PEG-Dsd1p was much less immunogenic compared to the unmodified enzyme. Intraperitoneal administration of PEG-Dsd1p was effective in decreasing the D-serine content in the mouse hippocampus. These findings suggest that PEG-Dsd1p may be a novel tool for lowering D-serine levels in vivo.
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Takada
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Isobe
authors.affiliation: Department of Anatomy, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Masataka
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kitaura
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hemmi
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan.
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Department of Anatomy, Keio University School of Medicine, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
authors.forename: Jumpei
authors.initials: J
authors.lastname: Sasabe
authors.affiliation: Department of Applied Molecular Biosciences, Graduate School of Bioagricultural Sciences, Nagoya University, Furou-chou, Chikusa, Nagoya, Aichi 464-8601, Japan. Electronic address: yosimura@agr.nagoya-u.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Yoshimura
mesh_terms: D000818:Animals; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D012695:L-Serine Dehydratase / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019163:Reducing Agents / Q000737:chemistry / Q000378:metabolism*; D012694:Serine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019163:Reducing Agents; D011092:Polyethylene Glycols; D012694:Serine; D012695:L-Serine Dehydratase
keywords: NMDA receptors; PEGylation; d-amino acid; d-serine; d-serine dehydratase