Tetrahydrobiopterin

Tetrahydrobiopterin
Clinical data
License data
Pregnancy
category
  • US: C (Risk not ruled out)
Routes of
administration		 By mouth
ATC code A16AX07 (WHO)
Legal status
Legal status
Pharmacokinetic data
Biological half-life 4 hours (healthy adults)
6–7 hours (PKU patients)
Identifiers
CAS Number 17528-72-2 YesY
PubChem (CID) 44257
IUPHAR/BPS 5276
DrugBank DB00360 YesY
ChemSpider 40270 YesY
ChEBI CHEBI:59560 YesY
ChEMBL CHEMBL1201774 N
Chemical and physical data
Formula C9H15N5O3
Molar mass 241.25 g/mol
3D model (Jmol) Interactive image
 NYesY (what is this?)  (verify)

Tetrahydrobiopterin (BH4, THB), also known as sapropterin, is a naturally occurring essential cofactor of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis of the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT), melatonin, dopamine, norepinephrine (noradrenaline), epinephrine (adrenaline), and is a cofactor for the production of nitric oxide (NO) by the nitric oxide synthases.[1] Chemically, its structure is that of a reduced pteridine derivative.

Medical use

Phenylketonuria

Sapropterin dihydrochloride may help lower phenylalanine levels in some people with phenylketonuria. It is FDA approved for this use along with dietary measures.[2] Most people however, have little or no benefit.[3]

Adverse effects

The most common adverse effects, observed in more than 10% of patients, include headache and a running or obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of patients.[4]

Interactions

No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitors like methotrexate and trimethoprim, and NO-enhancing drugs like nitroglycerin, molsidomine, minoxidil, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa can lead to increased excitability.[4]

Functions

Tetrahydrobiopterin has the following responsibilities as a cofactor:

Tetrahydrobiopterin has multiple roles in human biochemistry. One is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major monoamine neurotransmitters. Due to its role in the conversion of L-tyrosine into L-dopa, which is the precursor for dopamine, a deficiency in tetrahydrobiopterin can cause severe neurological issues unrelated to a toxic buildup of L-phenylalanine; dopamine is a vital neurotransmitter, and is the precursor of norepinephrine and epinephrine. Thus, a deficiency of BH4 can lead to systemic deficiencies of dopamine, norepinephrine, and epinephrine. In fact, one of the primary conditions that can result from GTPCH-related BH4 deficiency is dopamine-responsive dystonia;[5] currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

BH4 also serves as a catalyst for the production of nitric oxide. Among other things, nitric oxide is involved in vasodilation, which improves systematic blood flow. The role of BH4 in this enzymatic process is so critical that some research points to a deficiency of BH4 – and thus, of nitric oxide – as being a core cause of the neurovascular dysfunction that is the hallmark of circulation-related diseases such as diabetes.[6]

History

Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase (PAH).[7]

Biosynthesis

Tetrahydrobiopterin is biosynthesized from guanosine triphosphate (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I (GTPCH), 6-pyruvoyltetrahydropterin synthase (PTPS), and sepiapterin reductase (SR).[8]

Research

Other than PKU studies, tetrahydrobiopterin has participated in clinical trials studying other approaches to solving conditions resultant from a deficiency of tetrahydrobiopterin. These include autism, ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.[9][10] Experimental studies suggest that tetrahydrobiopterin regulates deficient production of nitric oxide in cardiovascular disease states, and contributes to the response to inflammation and injury, for example in pain due to nerve injury. A 2015 BioMarin-funded study of PKU patients found that those who responded to tetrahydrobiopterin also showed a reduction of ADHD symptoms.[11]

Autism

In 1997, a small pilot study was published on the efficacy of tetrahydrobiopterin (BH4) on relieving the symptoms of autism, which concluded that it "might be useful for a subgroup of children with autism" and that double-blind trials are needed, as are trials which measure outcomes over a longer period of time.[12] In 2010, Frye et al. published a paper which concluded that it was safe, and also noted that "several clinical trials have suggested that treatment with BH4 improves ASD symptomatology in some individuals."[13]

Cardiovascular disease

Since NO production is important in regulation of blood pressure and blood flow, thereby playing a significant role in cardiovascular diseases, tetrahydrobiopterin is a potential therapeutic target. In the endothelial cell lining of blood vessels, endothelial NOS is dependent on tetrahydrobiopterin availability.[14] Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial NOS function in experimental models of disease states such as diabetes,[15] atherosclerosis, and hypoxic pulmonary hypertension.[16] However, treatment of patients with existing coronary artery disease with oral tetrahydrobiopterin is limited by oxidation of tetrahydrobiopterin to the inactive form, dihydrobiopterin, with little benefit on vascular function .[17]

See also

References

  1. ↑ The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons; FOLIA HISTOCHEMICA ET CYTOBIOLOGICA; Author: Jarosław Całka; Department of Functional Morphology, Division of Animal Anatomy, University of Warmia and Mazury, Olsztyn, Poland; 2005; page 4
  2. ↑ "What are common treatments for phenylketonuria (PKU)?". NICHD. 2013-08-23. Retrieved 12 September 2016.
  3. ↑ Camp, KM; Parisi, MA; Acosta, PB; Berry, GT; Bilder, DA; Blau, N; Bodamer, OA; Brosco, JP; Brown, CS; Burlina, AB; Burton, BK; Chang, CS; Coates, PM; Cunningham, AC; Dobrowolski, SF; Ferguson, JH; Franklin, TD; Frazier, DM; Grange, DK; Greene, CL; Groft, SC; Harding, CO; Howell, RR; Huntington, KL; Hyatt-Knorr, HD; Jevaji, IP; Levy, HL; Lichter-Konecki, U; Lindegren, ML; Lloyd-Puryear, MA; Matalon, K; MacDonald, A; McPheeters, ML; Mitchell, JJ; Mofidi, S; Moseley, KD; Mueller, CM; Mulberg, AE; Nerurkar, LS; Ogata, BN; Pariser, AR; Prasad, S; Pridjian, G; Rasmussen, SA; Reddy, UM; Rohr, FJ; Singh, RH; Sirrs, SM; Stremer, SE; Tagle, DA; Thompson, SM; Urv, TK; Utz, JR; van Spronsen, F; Vockley, J; Waisbren, SE; Weglicki, LS; White, DA; Whitley, CB; Wilfond, BS; Yannicelli, S; Young, JM (June 2014). "Phenylketonuria Scientific Review Conference: state of the science and future research needs.". Molecular genetics and metabolism. 112 (2): 87–122. PMID 24667081.
  4. 1 2 Haberfeld, H, ed. (2009). Austria-Codex (in German) (2009/2010 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-196-X.
  5. ↑ "Genetics Home Reference: GCH1". National Institutes of Health.
  6. ↑ Wu, G; Meininger, CJ (2009). "Nitric oxide and vascular insulin resistance". BioFactors (Oxford, England). 35 (1): 21–7. doi:10.1002/biof.3. PMID 19319842.
  7. ↑ Kaufman, S (1 February 1958). "A New Cofactor Required for the Enzymatic Conversion of Phenylalanine to Tyrosine.". J. Biol. Chem. 230 (2): 931–939. PMID 13525410.
  8. ↑ Thony B, Auerbach G, Blau N (2000). "Tetrahydrobiopterin biosynthesis, regeneration and functions". Biochem J. 347 (1): 1–16. doi:10.1042/0264-6021:3470001. PMC 1220924Freely accessible. PMID 10727395.
  9. ↑ ClinicalTrials.gov: Search results for Kuvan
  10. ↑ "BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU". BioMarin Pharmaceutical Inc. 17 August 2010.
  11. ↑ Burton, B.; Grant, M. (2015-03-01). "A randomized, placebo-controlled, double-blind study of sapropterin to treat ADHD symptoms and executive function impairment in children and adults with sapropterin-responsive phenylketonuria". Molecular Genetics and Metabolism. 114 (3): 415–424. doi:10.1016/j.ymgme.2014.11.011. ISSN 1096-7206. PMID 25533024.
  12. ↑ Fernell, E.; Watanabe, Y.; Adolfsson, I.; Tani, Y.; Bergström, M.; Phd, P. H.; Md, A. L.; Phd., A. L. V. K. M. .; Phd., C. G. M. .; Phd., B. L. N. M. (2008). "Possible effects of tetrahydrobiopterin treatment in six children with autism – clinical and positron emission tomography data: A pilot study". Developmental Medicine & Child Neurology. 39 (5): 313. doi:10.1111/j.1469-8749.1997.tb07437.x.
  13. ↑ Frye, R. E.; Huffman, L. C.; Elliott, G. R. (2010). "Tetrahydrobiopterin as a novel therapeutic intervention for autism". Neurotherapeutics. 7 (3): 241–249. doi:10.1016/j.nurt.2010.05.004. PMC 2908599Freely accessible. PMID 20643376.
  14. ↑ Channon KM. (2004). "Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease". Trends Cardiovasc Med. 14 (8): 823–827. doi:10.1016/j.tcm.2004.10.003. PMID 15596110.
  15. ↑ Alp NJ, et al. (2003). "Tetrahydrobiopterin-dependent preservation of nitric oxide–mediated endothelial function in diabetes by targeted transgenic GTP–cyclohydrolase I overexpression". J Clin Invest. 112 (5): 725–735. doi:10.1172/JCI17786. PMC 182196Freely accessible. PMID 12952921.
  16. ↑ Khoo J, et al. (2005). "Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension". Circulation. 111 (16): 2126–2133. doi:10.1161/01.CIR.0000162470.26840.89. PMID 15824200.
  17. ↑ Cunnington C, et al. (2012). "Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treament in patients with coronary artery disease". Circulation. 125 (11): 1356–1366. doi:10.1161/CIRCULATIONAHA.111.038919. PMID 22315282.
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