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From SNPedia

Tetrahydrobiopterin (BH4) is an enzymatic cofactor in the production or conversion of amino acids and neurotransmitters. Genetic mutations in the DHFR, GCH1, PCBD1, PTS, QDPR and SPR can cause Tetrahydrobiopterin Deficiency. This deficiency has been linked to a less common form of phenylketonuria, the less severe hyperphenylalaninemia, and dopa responsive dystonia. It is also being studied for links to disorders such as ADHD, autism, hypertension and may also play a role in sensitivity to pain.

The Wikipedia Tetrahydrobiopterin entry has a good general summary. BH4.org has a lot more detail on BH4 linked disorders, diagnostic tests available, treatment options, and links to several scientific studies.

The document Neopterin and Biopterin provides a good technical overview of the production, use, and recycling of BH4. In particular, the graph on page 2 provides a good visualization of the BH4 cycle. There is also an overview of how defects in related genes affect testing results and treatment.


The first step is conversion of guanosine triphosphate to dihydroneopterin triphosphate via the GCH1 gene.

Dihydroneopterin triphosphate and magnesium are then converted to 6-pyruvoyl-tetrahydropterin via the PTS gene. Dihydroneopterin triphosphate can also degrade into neopterin.

6-pyruvoyl-tetrahydropterin and NADPH are converted to tetrahydrobiopterin (BH4) and NADP via the SPR gene. 6-pyruvoyl-tetrahydropterin can also degrade to sepiapterin and then dihydrobiopterin (BH2).

Dihydrobiopterin (BH2) and folate also convert to tetrahydrobiopterin (BH4) via the DHFR gene.

The GCHFR gene acts as feedback mechanism for GCH1 activity. GCHFR normally inhibits GCH1, but in the presence of phenylalanine it stimulates GCH1.


BH4 is a cofactor in the following processes needed to make neurotransmitters:

  • Conversion of Phenylalanine to Tyrosine by the Phenylalanine Hydroxylase (PAH) Gene
  • Conversion of Tyrosine and vitamin B6 to L-DOPA by the Tyrosine Hydroxylase (TH) Gene
  • Conversion of Tryptophan and vitamin B6 to 5-HTP by the Tryptophan Hydroxylase (TPH1) Gene

BH4 is also a cofactor in the conversion of arginine to citrulline and nitric oxide via the Nitric Oxide Synthase (NOS1, NOS2, NOS3) Genes.


In the above four conversions, the tetrahydrobiopterin (BH4) is converted to pterin-4a-carbinolamine which can be recycled into tetrahydrobiopterin (BH4) or degrade to primapterin and priapterin.

In the recycling process, pterin-4a-cabinolamine is converted to water and quinone-dihydrobiopterin (q-BH2) via the PCBD1 gene. quinone-dihydrobiopterin (q-BH2) and NADH are next converted to tetrahydrobiopterin (BH4) and NAD via the QDPR gene. Quinone-dihydrobiopterin can also degrade to biopterin.


L-DOPA is a precursor to dopamine which is further converted to norepinephrine and epinephrine. 5-HTP is a precursor to melatonin and serotonin. Treatment of tetrahydrobiopterin (BH4) problems depends on the affected gene, but typically involves some combination of supplementation with L-DOPA, 5-HTP, B4, and folate.

L-DOPA and 5-HTP are both commonly available in pharmaceutical form, while L-DOPA and 5-HTP are available as natural nutritional supplements in some countries. BH4 is also available in pharmaceutical form, though it is expensive and not as widely available currently. Folate is usually produced from folic acid, a commonly available nutritional supplement. Defects in the MTHFR gene may interfere in the production of folate, in which case supplementation of l-methylfolate may be used. L-methylfolate is available in pharmaceutical form and as a nutritional supplement.