PEGylated d-serine dehydratase as a d-serine reducing agent

Tomokazu Ito, Hiroe Takada, Keiko Isobe, Masataka Suzuki, Yasuyuki Kitaura, Hisashi Hemmi, Tsukasa Matsuda, Jumpei Sasabe, Tohru Yoshimura

Research output: Contribution to journalArticle

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 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.

Original languageEnglish
Pages (from-to)34-39
Number of pages6
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume116
DOIs
Publication statusPublished - 2014 Oct 9

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Keywords

  • D-amino acid
  • D-serine
  • D-serine dehydratase
  • NMDA receptors
  • PEGylation

ASJC Scopus subject areas

  • Analytical Chemistry
  • Drug Discovery
  • Pharmaceutical Science
  • Spectroscopy
  • Clinical Biochemistry

Cite this

Ito, T., Takada, H., Isobe, K., Suzuki, M., Kitaura, Y., Hemmi, H., Matsuda, T., Sasabe, J., & Yoshimura, T. (2014). PEGylated d-serine dehydratase as a d-serine reducing agent. Journal of Pharmaceutical and Biomedical Analysis, 116, 34-39. https://doi.org/10.1016/j.jpba.2014.12.044