TY - JOUR
T1 - PEGylated d-serine dehydratase as a d-serine reducing agent
AU - Ito, Tomokazu
AU - Takada, Hiroe
AU - Isobe, Keiko
AU - Suzuki, Masataka
AU - Kitaura, Yasuyuki
AU - Hemmi, Hisashi
AU - Matsuda, Tsukasa
AU - Sasabe, Jumpei
AU - Yoshimura, Tohru
N1 - Funding Information:
The authors thank Professor Kenji Hamase (Kyushu University, Japan) and Shiseido Co. Ltd., for their technical support. This work was supported in part by the Grant-in-Aid for Young Scientists (B) 24780098 (to T.I.), Novozymes Japan Research Fund (to T.I.) and Grant-in-Aid for Scientific Research 25292059 (to T.Y.) from the Japan Society for the Promotion of Science (JSPS). This work was also supported by the Program for Promotion of Basic and Applied Researches for Innovation in Bio-oriented Industry (BRAIN) (to T.Y.).
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/12/10
Y1 - 2015/12/10
N2 - 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 cerevisiae d-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 3.8. h to 22.4. h. 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.
AB - 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 cerevisiae d-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 3.8. h to 22.4. h. 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.
KW - D-amino acid
KW - D-serine
KW - D-serine dehydratase
KW - NMDA receptors
KW - PEGylation
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U2 - 10.1016/j.jpba.2014.12.044
DO - 10.1016/j.jpba.2014.12.044
M3 - Article
C2 - 25617179
AN - SCOPUS:84945461713
SN - 0731-7085
VL - 116
SP - 34
EP - 39
JO - Journal of Pharmaceutical and Biomedical Analysis
JF - Journal of Pharmaceutical and Biomedical Analysis
ER -