Tetrahydrobiopterin

Tetrahydrobiopterin

Systematic (IUPAC) name
(6R)-2-Amino-6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4(1H)-pteridinone
Identifiers
CAS number	17528-72-2
ATC code	A16AX07
PubChem	44257
ChemSpider	1093
Chemical data
Formula	C9H15N5O3
Mol. mass	241.25
Pharmacokinetic data
Bioavailability	?
Metabolism	?
Half life	?
Excretion	?
Therapeutic considerations
Licence data	US FDA:link
Pregnancy cat.	C(US)
Legal status	℞-only(US)
Routes	Oral
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Tetrahydrobiopterin (THB, BH₄; Kuvan) or sapropterin, is a naturally occurring nutrient and essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine (5-HT)), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and nitric oxide (NO).

History

THB was discovered to play a role as an enzymatic cofactor by Seymour Kaufman. The first enzyme found to use THB was phenylalanine hydroxylase (PAH).^[1]

Biosynthesis

THB is biosynthesized from guanosine triphosphate (GTP) by three chemical reactions, those of which are mediated by the enzymes (GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SPR).^[2]

Functions

THB has the following responsibilities as a cofactor:

• Tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP)
• Phenylalanine hydroxylase (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
• Tyrosine hydroxylase (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
• Nitric oxide synthase (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO)
• Glyceryl ether monooxygenase (GEMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol

Significance

A deficit in THB biosynthesis and/or regeneration results in phenylketonuria (PKU) from excess L-phenylalanine concentrations or hyperphenylalaninemia (HPA), as well as monoamine and nitric oxide neurotransmitter deficiency or chemical imbalance. The chronic presence of PKU can result in severe brain damage, including symptoms of mental retardation, microcephaly, speech impediments such as stuttering, slurring, and lisps, seizures or convulsions, and behavioral abnormalities, among other effects.

THB, developed by BioMarin under the brand name Kuvan and approved by the United States (U.S.) Food and Drug Administration (FDA) on December 13, 2007, is a synthetic preparation of the dihydrochloride salt of the substance, used in the treatment of PKU.^[3] HPA due to THB deficiency-mediated PKU.

See also

• Tetrahydrobiopterin Deficiency (THBD, BH₄D)
• Phenylketonuria (PKU)

References

External links

• Coenzyme tetrahydrobiopterin (BH₄)
• Tetrahydrobiopterin website
• Kuvan website, run by BioMarin
• Prescribing information
• Information on phenylketunaria (PKU)