Biochemistry behind phenylketonuria

Metabolic pathway of Phenylalanine

L-Phenylalanine is an essential amino acid that can be taken from diet and is needed for protein synthesis. Phenylalanine hydroxylase (PAH) requires cofactor, tetrahydrobiopterin (BH4) and oxygen to work. PAH together with BH4 catalyses the hydroxylation of L-Phe to L-Tyr.L- Tyr is then converted to Fumarate and then form CO2 and H2O. This metabolism mainly occurs in the liver.

Lack of PAH activity due to genetic defect PAH gene
However, when there is non-functional PAH, L-Phe cannot be converted to L-Tyr. L-Phe will be metabolise by the other 2 pathways, provided that there is no functional PAH. In the other 2 pathways, L-Phe will go through transamination or decarboxylation to form Phenylacetylglutamate, o-hydroxyphenylacetate or phenyl-lactate. The metabolites in the pathway will be released into the bloodstream and bring to the brain. Decarboxylation of L-Phe causes the amount of phenylacetylglutamate(very toxic) to increase. As it accumulates, it can result in alteration in mental status and cognitive impairment. Accumulation of phenyl-lactate will also cause grownth retardation as it causes the myelin level in the verebral hemispheres and the cerebellum to fall. This resulted in the mental retardation in classic PKU.


Lack of PAH activity due to de novo synthesis of BH4 

Classic PKU can also be resulted if the GTP cyclohydrolase I and pyruvoyl tetrahydropterin synthase is not functional as BH4 cannot be formed in the de novo synthesis of BH4.

Lack of PAH activity due to faulty BH4 regeneration pathway- Account for 1-3% of hyperphenylalaninemia
Any mutation in structures of BH4 can lead to a rare form of PKU. This type of PKU is known as ''malignant'' PKU due to the progressive deterioration in neurological function. This deterioration cannot be removed by limiting the phenylalanine dietary intake. Consequence of such problem is defection in neurotransmission. While L-Phe go through the dehydroxylation to form L-Tyr, BH4 is oxidized to BH2 (dihydrobiopterin) by PAH. BH4 is then regenerated by dihydropholate reductase (DHPR). 
   

Regeneration of BH4 from BH2

References:

1. Introduction to Phenylketonuria. Retrived July 1, 2012, from http://www.uic.edu/classes/phar/phar332/Clinical_Cases/aa%20metab%20cases/PKU%20Cases/PKU%20biochem%20intro.htm

2. Robin A Williams,Cyril DS Mamotte, John R Burnett. (2008). Phenylketonuria: An Inborn Error of Phenylalanine Metabolism. National Center for Biotechnology Information. Retrieved July 2, 2012, from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2423317/

3. Nariman Hossein-Javaheri. (2012). Phenylketonuria. Tangient LLC. Retrieved July 10, 2012, from https://neurowiki2012.wikispaces.com/Phenylketonuria