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 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 .