Phenylalanine ammonia-lyase modified with polyethylene glycol: potential therapeutic agent for phenylketonuria.
Phenylketonuria (PKU) is an autosomal recessive genetic disease caused by the defects in the phenylalanine hydroxylase (PAH) gene. Individuals homozygous for defective PAH alleles show elevated levels of systemic phenylalanine and should be under strict dietary control to reduce the risk of neuronal damage associated with high levels of plasma phenylalanine. Researchers predict that plant phenylalanine ammonia-lyase (PAL), which converts phenylalanine to nontoxic t-cinnamic acid, will be an effective therapeutic enzyme for the treatment of PKU. The problems of this potential enzyme therapy have been the low stability in the circulation and the antigenicity of the plant enzyme. Recombinant PAL originated from parsley (Petroselinum crispum) chemically conjugated with activated PEG2 [2,4-bis(O-methoxypolyethyleneglycol)-6-chloro-s-triazine] showed greatly enhanced stability in the circulation and was effective in reducing the plasma concentration of phenylalanine in the circulation of mice. PEG-PAL conjugate will be an effective therapeutic enzyme for the treatment of PKU.
Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan.
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K
Ikeda
E
E
Schiltz
T
T
Fujii
M
M
Takahashi
K
K
Mitsui
Y
Y
Kodera
A
A
Matsushima
Y
Y
Inada
G E
GE
Schulz
H
H
Nishimura
D000818:Animals; D004789:Enzyme Activation / Q000502:physiology; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D028528:Petroselinum / Q000201:enzymology; D010649:Phenylalanine / Q000097:blood* / Q000187:drug effects*; D010650:Phenylalanine Ammonia-Lyase / Q000008:administration & dosage* / Q000737:chemistry; D010661:Phenylketonurias / Q000097:blood; D011092:Polyethylene Glycols / Q000737:chemistry*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000737:chemistry; D013329:Structure-Activity Relationship; D013997:Time Factors
D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D010649:Phenylalanine; D010650:Phenylalanine Ammonia-Lyase