Phenylalanine 4-hydroxylase

Phenylalanine 4-hydroxylase (PAH) is an enzyme that in humans is encoded by the PAH gene. This enzyme is crucial in the metabolism of the amino acid phenylalanine, converting it into tyrosine, another amino acid. This reaction is a key step in the phenylalanine catabolic pathway, which takes place primarily in the liver. The activity of phenylalanine 4-hydroxylase is dependent on the presence of the cofactor tetrahydrobiopterin (BH4), molecular oxygen, and iron (Fe2+).

Function

Phenylalanine 4-hydroxylase plays a vital role in amino acid degradation, specifically in the metabolic pathway that converts phenylalanine to tyrosine. Tyrosine is a precursor for the synthesis of neurotransmitters such as dopamine, norepinephrine, and epinephrine, as well as for melanin, the pigment responsible for the color of skin and hair. Therefore, the activity of this enzyme is essential for normal brain development and function.

Genetics

The PAH gene is located on chromosome 12 (12q23.2) and consists of 13 exons and 12 introns. Mutations in the PAH gene can lead to a deficiency of the enzyme, a condition known as Phenylketonuria (PKU). PKU is an inherited disorder that, if left untreated, can cause intellectual disability, seizures, behavioral problems, and mental disorders.

Clinical Significance

A deficiency in phenylalanine 4-hydroxylase activity leads to the accumulation of phenylalanine in the blood and brain, which can be toxic to brain development and function. The diagnosis of PKU is typically made through newborn screening, allowing for early dietary management to control phenylalanine levels in the blood. Treatment usually involves a diet low in phenylalanine, supplemented with tyrosine to support normal growth and development.

Biochemical Properties

Phenylalanine 4-hydroxylase is a monomeric enzyme that requires tetrahydrobiopterin (BH4), molecular oxygen, and iron (Fe2+) for its catalytic activity. The enzyme is highly specific for its substrate, phenylalanine, and is regulated by a number of factors, including the availability of its cofactor BH4 and the levels of phenylalanine in the blood.

See Also

• Amino acid metabolism
• Inborn error of metabolism
• Tyrosine hydroxylase