PKU Biochemistry
Phenylalanine hydroxylase: targeting the underlying enzymatic defect in PKU
In phenylketonuria (PKU), elevated phenylalanine (Phe) levels arise from defects in the phenylalanine hydroxylase (PAH) enzyme, which is involved in the metabolism of Phe to tyrosine.27
Normal phenylalanine hydroxylation primarily takes place in the liver.27 The cofactor tetrahydrobiopterin (BH4) activates PAH to convert Phe to tyrosine, making it an essential part of Phe metabolism. This triggers the hydroxylation reactions for the production of catecholamines and neurotransmitters (namely, the metabolism of tyrosine to dopamine and, subsequently, norepinephrine and epinephrine). BH4 is also a cofactor for the enzyme involved in the metabolism of tryptophan to serotonin.27
In PKU, the underlying defect in the PAH enzyme interrupts Phe metabolism to create a cascade of detrimental effects, as shown in the diagram below.27 The resulting elevation in blood Phe concentration can result in brain toxicity; likewise, the halt in tyrosine availability affects the production of dopamine, norepinephrine, and epinephrine.27
There is a secondary Phe metabolism pathway that converts Phe to phenylpyruvate, a phenylketone, and is catalyzed by aminotransferases. In the absence or underactivity of PAH, a large amount of Phe is converted to phenylpyruvate, resulting in a buildup of phenylpyruvate in bodily fluids. It is the abundance of this phenylketone that gives the disease its name.15
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