Microorganisms engineered to reduce hyperphenylalaninemia
Genetically engineered bacteria, pharmaceutical compositions thereof, and methods of modulating and treating diseases associated with hyperphenylalaninemia are disclosed.
1. A mutant phenylalanine ammonia lyase (PAL) polypeptide comprising one or more mutations at amino acid positions selected from S92, H133, I167, L432, V470, A433, A263, K366 and L396 compared to a wildtype Photorhabdus luminescens PAL comprising SEQ ID NO: 1.
2. The mutant PAL polypeptide of claim 1 , wherein the mutations comprise:
(a) S92G; H133M; I167K; L432I; V470A;
(b) S92G; H133F; A433S; V470A; or
(c) S92G; H133F; A263T; V470A.
3. The mutant PAL polypeptide of claim 1 , wherein the polypeptide exhibits increased ability to metabolize phenylalanine compared to the wildtype PAL.
4. The mutant PAL polypeptide of claim 1 , wherein the polypeptide exhibits at least two-fold increase in the ability to metabolize phenylalanine compared to the wildtype PAL.
5. The mutant PAL polypeptide of claim 1 , wherein the polypeptide exhibits at least three-fold increase in the ability to metabolize phenylalanine compared to the wildtype PAL.
6. The mutant PAL polypeptide of claim 1 , wherein the polypeptide exhibits at least four-fold increase in the ability to metabolize phenylalanine compared to the wildtype PAL.
7. The mutant PAL polypeptide of claim 1 , wherein the polypeptide exhibits at least five-fold increase in the ability to metabolize phenylalanine compared to the wildtype PAL.
8. A composition comprising the mutant PAL polypeptide of claim 1 .