BH4 (tetrahydrobiopterin) plays an important role in the activity of the enzyme that is dysfunctional, or not working properly, in people with phenylketonuria (PKU).
Here is more information about BH4 and how it may be able to help some PKU patients.
What is BH4 and how is it related to PKU?
BH4 is a molecule that the body produces to act as a cofactor. A cofactor enables or enhances the activity of enzymes.
One of the enzymes that works with BH4 is phenylalanine hydroxylase (PAH). This is the enzyme that is not present or does not work correctly in PKU. The PAH enzyme is normally responsible for converting the amino acid phenylalanine (Phe) into another amino acid, tyrosine. Amino acids are the building blocks of proteins. Without enough functioning PAH enzyme, Phe builds up in the body and leads to the symptoms of PKU.
Researchers don’t know the exact way in which BH4 interacts with the PAH enzyme. However, they think that it helps to stabilize the enzyme and keep it active. In normal conditions, BH4 concentration regulates the activity of PAH, with higher concentrations leading to more activity and more Phe conversion.
A condition called tetrahydrobiopterin deficiency results in symptoms similar to PKU. Mutations in one of several genes that encode for enzymes that make or recycle BH4 cause this condition. Low levels of BH4 in these patients reduce the activity of the PAH enzyme. This ultimately leads to high Phe levels like in PKU.
How can it help treat PKU?
The PAH enzyme consists of four identical pieces. If there is a fault in any of the pieces, they cannot fit together and work properly. BH4 may help these pieces fold correctly so that they can come together and form a more functional PAH enzyme.
Since BH4 can regulate the activity of the PAH enzyme, researchers thought that increasing its levels may help treat some people with PKU. Through testing in multiple clinical trials, they demonstrated the efficacy of a synthetic form of BH4 called sapropterin dihydrochloride.
Sapropterin dihydrochloride is currently approved and sold under the brand name Kuvan, developed by BioMarin.
The treatment may benefit 20 to 30% of patients with PKU. There are several factors that can influence the treatment’s efficacy. Since it is difficult to predict how a patient will respond, doctors usually prescribe it for a trial period while they monitor Phe levels in the patient’s blood. If the Phe levels drop significantly during the trial period, patients are considered to be responsive to the BH4 treatment.
Last updated: Feb. 18, 2021
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