Variants and chemically-modified variants of phenylalanine ammonia-lyase
View Patent ↗The present invention pertains to the use of the protein phenylalanine ammonia-lyase, as well as the biologically-active derivatives of the said protein for preventing or treating diseases associated with a phenylalanine imbalance in a human or animal body. More particularly, the present invention relates to the therapeutic use of the above-cited molecules for preventing or treating a phenylalanine imbalance in vivo. This invention also deals with therapeutic compositions comprising a pharmaceutically active amount of the above-described therapeutic molecules as well as with therapeutic methods using the said therapeutic compositions. Finally, the present invention relates to processes for selecting more therapeutically-effective variants of said protein as well as to the selected variants themselves.
1. A phenylalanine ammonia lyase (PAL) comprising a mutant Rhodosporidium toruloides PAL, wherein said PAL has a mutation selected from the group consisting of: R91K, H137K and combinations thereof.
2. The PAL of claim 1 , wherein the amino acid residue is replaced by site-directed mutagenesis, random mutagenesis, or by point mutagenesis.
3. The PAL of claim 1 , further comprising pegylation.
4. The PAL of claim 3 , wherein the PAL has a phenylalanine-converting activity greater than the wild-type PAL.
5. The PAL of claim 4 , wherein the PAL has the phenylalanine-converting activity at least 20% greater than the wild-type PAL.
6. A composition comprising the PAL of claim 1 or 3 .
7. A method for treating an amino acid metabolism disease by administering the composition of claim 6 to a patient in need thereof, wherein said amino acid metabolism disease is selected from the group consisting of phenylketonuria, hyperphenylalanemia, tyrosineamia and histidinemia.