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Revision as of 12:38, 10 January 2012 editBeetstra (talk | contribs)Edit filter managers, Administrators172,031 edits Saving copy of the {{drugbox}} taken from revid 467571657 of page Tetrahydrobiopterin for the Chem/Drugbox validation project (updated: 'ChEMBL').  Latest revision as of 22:34, 18 October 2024 edit Citation bot (talk | contribs)Bots5,391,853 edits Alter: journal, pages. Removed parameters. Formatted dashes. | Use this bot. Report bugs. | Suggested by Spinixster | Category:Chemicals using indexlabels | #UCB_Category 739/831 
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{{Short description|Chemical compound}}
{{ambox | text = This page contains a copy of the infobox ({{tl|drugbox}}) taken from revid of page ] with values updated to verified values.}}
{{Use dmy dates|date=March 2020}}
{{Drugbox
{{Redirect|BH4|the anion|Borohydride|the edition of the Hebrew Bible|Biblia Hebraica Stuttgartensia}}
| Verifiedfields = changed
{{Infobox drug
| Watchedfields = changed
| Verifiedfields = changed
| verifiedrevid = 398957700
| verifiedrevid = 470604083
| IUPAC_name = (6''R'')-2-Amino-6--5,6,7,8-tetrahydropteridin-4(1''H'')-one
| drug_name =
| image = Tetrahydrobiopterin structure.png
| INN = sapropterin
| type = <!-- empty -->
| image = (6R)-Tetrahydrobiopterin structure.svg
| width =
| alt =
| caption =
| JAN = Sapropterin hydrochloride
| USAN = Sapropterin dihydrochloride


<!--Clinical data--> <!-- Clinical data -->| pronounce =
| tradename = | tradename = Kuvan, Biopten
| Drugs.com = {{drugs.com|monograph|sapropterin-dihydrochloride}}
| licence_US = Kuvan
| MedlinePlus = a608020
| pregnancy_US = C
| licence_CA = <!-- Health Canada may use generic or brand name (generic name preferred) -->
| legal_US = Rx-only
| licence_EU = yes
| routes_of_administration = Oral
| DailyMedID = Sapropterin
| licence_US = Sapropterin
| pregnancy_AU = B1
| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Sapropterin (Kuvan) Use During Pregnancy | website=Drugs.com | date=17 May 2019 | url=https://www.drugs.com/pregnancy/sapropterin.html | access-date=4 March 2020}}</ref>
| pregnancy_category =
| routes_of_administration = ]
| class =
| ATCvet =
| ATC_prefix = A16
| ATC_suffix = AX07
| ATC_supplemental = <!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment = <ref name="Kuvan CA Product information" />
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = <!-- GSL, P, POM, CD, CD Lic, CD POM, CD No Reg POM, CD (Benz) POM, CD (Anab) POM or CD Inv POM / Class A, B, C -->
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Kuvan FDA label" />
| legal_EU = Rx-only
| legal_EU_comment = <ref name="Kuvan EPAR" />
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = Rx-only


<!--Pharmacokinetic data--> <!-- Pharmacokinetic data -->| bioavailability =
| protein_bound =
| metabolism =
| metabolites =
| onset =
| elimination_half-life = 4 hours (healthy adults)<br />6–7 hours (] patients) | elimination_half-life = 4 hours (healthy adults)<br />6–7 hours (] patients)
| duration_of_action =

<!--Identifiers--> | excretion = <!-- Identifiers -->
| index2_label = as salt
| CASNo_Ref = {{cascite|correct|CAS}}
| CAS_number_Ref = {{cascite|correct|??}} | CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 17528-72-2 | CAS_number = 62989-33-7
| CAS_number2 = 69056-38-8
| ATC_prefix = A16
| CAS_supplemental =
| ATC_suffix = AX07
| PubChem = 44257 | PubChem = 135398654
| IUPHAR_ligand = 5276
| DrugBank_Ref = {{drugbankcite|changed|drugbank}}
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00360
| DrugBank = DB00360
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| DrugBank2 = DBSALT001133
| ChemSpiderID = 40270
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChemSpiderID = 40270
| ChEBI = 59560
| ChemSpiderID2 = 552166
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| UNII_Ref =
| ChEMBL = <!-- blanked - oldvalue: 1201774 -->
| C=9 | H=15 | N=5 | O=3 | UNII = EGX657432I
| KEGG_Ref =
| molecular_weight = 241.25 g/mol
| KEGG = D08505
| smiles = O=C2\N=C(/NC=1NC(NC=12)(O)(O)C)N
| KEGG2_Ref =
| InChI = 1/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1
| KEGG2 = D01798
| InChIKey = FNKQXYHWGSIFBK-RPDRRWSUBX
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 59560
| StdInChI = 1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1
| ChEBI2 = 32120
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| ChEMBL_Ref = {{ebicite|changed|EBI}}
| StdInChIKey = FNKQXYHWGSIFBK-RPDRRWSUSA-N
| ChEMBL = 1201774
| ChEMBL2 = 1201775
| NIAID_ChemDB =
| PDB_ligand = H4B
| synonyms = <!-- Chemical and physical data -->
| IUPAC_name = (6''R'')-2-Amino-6--5,6,7,8-tetrahydropteridin-4(1''H'')-one
| C = 9
| H = 15
| N = 5
| O = 3
| SMILES = CC(C(C1CNC2=C(N1)C(=O)N=C(N2)N)O)O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = FNKQXYHWGSIFBK-RPDRRWSUSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}} }}

'''Tetrahydrobiopterin''' ('''BH<sub>4</sub>''', '''THB'''), also known as '''sapropterin''' (INN),<ref>{{cite web | title=Sapropterin | website=Drugs.com | date=28 February 2020 | url=https://www.drugs.com/international/sapropterin.html | access-date=4 March 2020 }}</ref><ref>{{cite web | title=International Non-proprietary Names for Pharmaceutical Substances (INN) | website=Fimea | url=https://www.fimea.fi/web/en/supervision/legislation/european_pharmacopoeia/international-non-proprietary-names-for-pharmaceutical-substances-inn- | access-date=4 March 2020 }}</ref> is a ] of the three ] enzymes,<ref name=Cara>{{cite journal | vauthors = Kappock TJ, Caradonna JP | title = Pterin-Dependent Amino Acid Hydroxylases | journal = Chemical Reviews | volume = 96 | issue = 7 | pages = 2659–2756 | date = November 1996 | pmid = 11848840 | doi = 10.1021/CR9402034 }}</ref> used in the degradation of amino acid ] and in the ] of the ]s ] (5-hydroxytryptamine, 5-HT), ], ], ] (noradrenaline), ] (adrenaline), and is a cofactor for the production of ] (NO) by the nitric oxide synthases.<ref> Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633 </ref><ref>{{cite journal | vauthors = Całka J | title = The role of nitric oxide in the hypothalamic control of LHRH and oxytocin release, sexual behavior and aging of the LHRH and oxytocin neurons | journal = Folia Histochemica et Cytobiologica | volume = 44 | issue = 1 | pages = 3–12 | year = 2006 | pmid = 16584085 | url = http://czasopisma.viamedica.pl/fhc/article/view/4581 }}</ref> Chemically, its structure is that of a (dihydropteridine reductase) reduced ] derivative (quinonoid dihydrobiopterin).<ref>{{Cite book| vauthors = Bhagavan NV |title=Essentials of Medical Biochemistry With Clinical Cases, 2nd Edition|publisher=Elsevier|year=2015|isbn=978-0-12-416687-5|location=USA|pages=256}}</ref>{{citation needed|date=March 2020}}

== Medical use ==
Tetrahydrobiopterin is available as a tablet for ] in the form of ''sapropterin dihydrochloride'' (BH4*2HCL).<ref>{{cite journal | vauthors = Schaub J, Däumling S, Curtius HC, Niederwieser A, Bartholomé K, Viscontini M, Schircks B, Bieri JH | display-authors = 6 | title = Tetrahydrobiopterin therapy of atypical phenylketonuria due to defective dihydrobiopterin biosynthesis | journal = Archives of Disease in Childhood | volume = 53 | issue = 8 | pages = 674–6 | date = August 1978 | pmid = 708106 | pmc = 1545051 | doi = 10.1136/adc.53.8.674 }}</ref><ref name="Kuvan FDA label">{{cite web | title=Kuvan- sapropterin dihydrochloride tablet Kuvan- sapropterin dihydrochloride powder, for solution Kuvan- sapropterin dihydrochloride powder, for solution | website=DailyMed | date=13 December 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=af38711e-8873-4790-a92d-4d583e23fb89 | access-date=4 March 2020 }}</ref><ref name="Kuvan EPAR">{{cite web | title=Kuvan EPAR | website=] (EMA) | date=4 March 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/kuvan | access-date=4 March 2020}}</ref> It was approved for use in the United States as a tablet in December 2007<ref>{{cite web | title=Drug Approval Package: Kuvan (Sapropterin Dihydrochloride) NDA #022181 | website=U.S. ] (FDA) | date=24 March 2008 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181TOC.cfm | access-date=4 March 2020}}
*{{lay source |template=cite web |author=Daniel A. Shames |date=13 December 2007 |url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/022181s000_SumR.pdf |title=Summary Review: Application number: 22-181 |website=U.S. Food and Drug Administration}}</ref><ref name="BioMarin Kuvan" /> and as a powder in December 2013.<ref>{{cite web | title=Drug Approval Package: Kuvan Powder for Oral Solution (Sapropterin Dihydrochloride) NDA #205065 | website=U.S. ] (FDA) | date=28 February 2014 | url=https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/205065Orig1s000TOC.cfm | access-date=4 March 2020}}</ref><ref name="BioMarin Kuvan" /> It was approved for use in the European Union in December 2008,<ref name="Kuvan EPAR" /> Canada in April 2010,<ref name="Kuvan CA Product information">{{cite web | title=Kuvan Product information | website=Health Canada | date=25 April 2012 | url=https://health-products.canada.ca/dpd-bdpp/info.do?lang=en&code=83577 | access-date=24 June 2022}}</ref> and Japan in July 2008.<ref name="BioMarin Kuvan" /> It is sold under the brand names '''Kuvan''' and '''Biopten'''.<ref name="Kuvan EPAR" /><ref name="Kuvan FDA label" /><ref name="BioMarin Kuvan">{{cite web | title=Kuvan (sapropterin dihydrochloride) Tablets and Powder for Oral Solution for PKU | website=BioMarin | url=https://www.biomarin.com/products/kuvan | access-date=4 March 2020}}</ref> The typical cost of treating a patient with Kuvan is {{US$|100,000}} per year.<ref>{{cite web|url=https://www.forbes.com/sites/matthewherper/2016/07/28/from-rare-to-great/|title=How Focusing On Obscure Diseases Made BioMarin A $15 Billion Company| vauthors = Herper M |date=28 July 2016|website=]|access-date=2017-10-09}}</ref> ] holds the patent for Kuvan until at least 2024, but ] has a right to produce a generic version by 2020.<ref>{{cite web|url=http://www.prnewswire.com/news-releases/biomarin-announces-kuvan-sapropterin-dihydrochloride-patent-challenge-settlement-300439214.html|title=BioMarin Announces Kuvan (sapropterin dihydrochloride) Patent Challenge Settlement|publisher=BioMarin Pharmaceutical Inc. | via=]|date=2017-04-13|access-date=2017-10-09}}</ref>

Sapropterin is indicated in ] caused by ] (GTPCH) deficiency, or ] (PTPS) deficiency.<ref>{{cite web|url=https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/|title=Tetrahydrobiopterin Deficiency|website=] (NORD)|access-date=2017-10-09}}</ref> Also, BH4*2HCL is FDA approved for use in ] (PKU), along with dietary measures.<ref name=NIH2013Tx>{{cite web|title=What are common treatments for phenylketonuria (PKU)?|url=https://www.nichd.nih.gov/health/topics/pku/conditioninfo/Pages/treatments.aspx|website=NICHD|access-date=12 September 2016|date=2013-08-23}}</ref> However, most people with PKU have little or no benefit from BH4*2HCL.<ref>{{cite journal | vauthors = 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 | display-authors = 6 | title = Phenylketonuria Scientific Review Conference: state of the science and future research needs | journal = Molecular Genetics and Metabolism | volume = 112 | issue = 2 | pages = 87–122 | date = June 2014 | pmid = 24667081 | doi = 10.1016/j.ymgme.2014.02.013 | url = https://zenodo.org/record/1259489 }}</ref>

== Adverse effects ==
The most common ], observed in more than 10% of people, include headache and a running or obstructed nose. Diarrhea and vomiting are also relatively common, seen in at least 1% of people.<ref name="AustriaCodex">{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|date=1 March 2017|language=German|at=Kuvan 100 mg-Tabletten}}</ref>

== Interactions ==
No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with ]s like ] and ], and NO-enhancing drugs like ], ], ], and ]. Combination of tetrahydrobiopterin with ] can lead to increased excitability.<ref name="AustriaCodex" />

== Functions ==
Tetrahydrobiopterin has multiple roles in human biochemistry. The major one is to convert amino acids such as phenylalanine, tyrosine, and tryptophan to precursors of dopamine and serotonin, major ] neurotransmitters.<ref> Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633 </ref> It works as a ], being required for an enzyme's activity as a catalyst, mainly ]s.<ref name=Cara/>

===Cofactor for tryptophan hydroxylases===
{{further|Tryptophan hydroxylase}}
Tetrahydrobiopterin is a cofactor for ] (TPH) for the conversion of ] (TRP) to ] (5-HTP).

===Cofactor for phenylalanine hydroxylase===
] (PAH) catalyses the conversion of ] (PHE) to ] (TYR). Therefore, a deficiency in tetrahydrobiopterin can cause a toxic buildup of L-phenylalanine, which manifests as the severe neurological issues seen in ].

===Cofactor for tyrosine hydroxylase===
] (TH) catalyses the conversion of L-tyrosine to ] (DOPA), which is the precursor for ]. Dopamine is a vital ], and is the precursor of ] and ]. 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 ];<ref>{{cite web|url=http://ghr.nlm.nih.gov/gene/GCH1|title=Genetics Home Reference: GCH1|publisher=] }}</ref> currently, this condition is typically treated with ], which directly restores dopamine levels within the brain.

===Cofactor for nitric oxide synthase===
] (NOS) catalyses the conversion of a guanidino nitrogen of ] (L-Arg) to ] (NO). Among other things, nitric oxide is involved in ], 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 ].<ref>{{cite journal | vauthors = Wu G, Meininger CJ | title = Nitric oxide and vascular insulin resistance | journal = BioFactors | volume = 35 | issue = 1 | pages = 21–7 | year = 2009 | pmid = 19319842 | doi = 10.1002/biof.3 | s2cid = 29828656 | author-link1 = Guoyao Wu }}</ref> As a co-factor for nitric oxide synthase, tetrahydrobiopterin supplementation has shown beneficial results for the treatment of ] in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.<ref name="pmid29596860">{{cite journal | vauthors = Yuyun MF, Ng LL, Ng GA | title=Endothelial dysfunction, endothelial nitric oxide bioavailability, tetrahydrobiopterin, and 5-methyltetrahydrofolate in cardiovascular disease. Where are we with therapy? | journal= Microvascular Research | volume=119 | pages=7–12 | year=2018 | doi= 10.1016/j.mvr.2018.03.012 | pmid=29596860}}</ref>

===Cofactor for ether lipid oxidase===
Ether lipid oxidase (], AGMO) catalyses the conversion of ] to ].

== History ==
Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is ] (PAH).<ref>{{cite journal | vauthors = Kaufman S | title = A new cofactor required for the enzymatic conversion of phenylalanine to tyrosine | journal = The Journal of Biological Chemistry | volume = 230 | issue = 2 | pages = 931–9 | date = February 1958 | doi = 10.1016/S0021-9258(18)70516-4 | pmid = 13525410 | doi-access = free }}</ref>

== Biosynthesis and recycling ==
Tetrahydrobiopterin is biosynthesized from ] (GTP) by three chemical reactions mediated by the enzymes ] (GTPCH), ] (PTPS), and ] (SR).<ref name="pmid10727395">{{cite journal | vauthors = Thöny B, Auerbach G, Blau N | title = Tetrahydrobiopterin biosynthesis, regeneration and functions | journal = The Biochemical Journal | volume = 347 | issue = Pt 1 | pages = 1–16 | date = April 2000 | pmid = 10727395 | pmc = 1220924 | doi = 10.1042/0264-6021:3470001 }}</ref>

BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2, respectively. Research shows that ascorbic acid (also known as ascorbate or ]) can reduce BH3 radical into BH4,<ref>{{cite journal | vauthors = Kuzkaya N, Weissmann N, Harrison DG, Dikalov S | title = Interactions of peroxynitrite, tetrahydrobiopterin, ascorbic acid, and thiols: implications for uncoupling endothelial nitric-oxide synthase | journal = The Journal of Biological Chemistry | volume = 278 | issue = 25 | pages = 22546–54 | date = June 2003 | pmid = 12692136 | doi = 10.1074/jbc.M302227200 | doi-access = free }}</ref> preventing the BH3 radical from reacting with other free radicals (] and ] specifically). Without this recycling process, uncoupling of the ] (eNOS) enzyme and reduced bioavailability of the ] ] occur, creating a form of ].<ref>{{cite journal | vauthors = Muller-Delp JM | title = Ascorbic acid and tetrahydrobiopterin: looking beyond nitric oxide bioavailability | journal = Cardiovascular Research | volume = 84 | issue = 2 | pages = 178–9 | date = November 2009 | pmid = 19744948 | doi = 10.1093/cvr/cvp307 | doi-access = free }}</ref> Ascorbic acid is oxidized to ] during this process, although it can be recycled back to ascorbic acid.

Folic acid and its metabolites seem to be particularly important in the recycling of BH4 and NOS coupling.<ref>{{cite journal | vauthors = Gori T, Burstein JM, Ahmed S, Miner SE, Al-Hesayen A, Kelly S, Parker JD | title = Folic acid prevents nitroglycerin-induced nitric oxide synthase dysfunction and nitrate tolerance: a human in vivo study | journal = Circulation | volume = 104 | issue = 10 | pages = 1119–23 | date = September 2001 | pmid = 11535566 | doi = 10.1161/hc3501.095358 | doi-access = free }}</ref>

== 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 ], ],<ref> Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633 </ref> ], ], endothelial dysfunction, and ].<ref>{{cite web | url = http://www.clinicaltrials.gov/ct2/results?term=kuvan&pg=2 | work = ClinicalTrials.gov | publisher = U.S. National Library of Medicine | title = Search results for Kuvan }}</ref><ref>{{cite news |url= http://www.fiercebiotech.com/press-releases/biomarin-initiates-phase-3b-study-evaluate-effects-kuvan-neurophychiatric-symptoms-su |title=BioMarin Initiates Phase 3b Study to Evaluate the Effects of Kuvan on Neurophychiatric Symptoms in Subjects with PKU|date=17 August 2010|publisher=BioMarin Pharmaceutical Inc}}</ref> 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.<ref>{{cite journal | vauthors = Burton B, Grant M, Feigenbaum A, Singh R, Hendren R, Siriwardena K, Phillips J, Sanchez-Valle A, Waisbren S, Gillis J, Prasad S, Merilainen M, Lang W, Zhang C, Yu S, Stahl S | display-authors = 6 | title = 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 | journal = Molecular Genetics and Metabolism | volume = 114 | issue = 3 | pages = 415–24 | date = March 2015 | pmid = 25533024 | doi = 10.1016/j.ymgme.2014.11.011 | doi-access = free }}</ref>

===Depression===
In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date.<ref> Cavaleri et al. Blood concentrations of neopterin and biopterin in subjects with depression: A systematic review and meta-analysis ''Progress in Neuro-Psychopharmacology and Biological Psychiatry'' 2023. 120:110633. http://dx.doi.org/10.1016/j.pnpbp.2022.110633 </ref>

=== 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.<ref>{{cite journal | vauthors = Fernell E, Watanabe Y, Adolfsson I, Tani Y, Bergström M, Hartvig P, Lilja A, von Knorring AL, Gillberg C, Långström B | display-authors = 6 | title = Possible effects of tetrahydrobiopterin treatment in six children with autism--clinical and positron emission tomography data: a pilot study | journal = Developmental Medicine and Child Neurology | volume = 39 | issue = 5 | pages = 313–8 | date = May 1997 | pmid = 9236697 | doi = 10.1111/j.1469-8749.1997.tb07437.x | s2cid = 12761124 | doi-access = free }}</ref> In 2010, ] 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."<ref>{{cite journal | vauthors = Frye RE, Huffman LC, Elliott GR | title = Tetrahydrobiopterin as a novel therapeutic intervention for autism | journal = Neurotherapeutics | volume = 7 | issue = 3 | pages = 241–9 | date = July 2010 | pmid = 20643376 | pmc = 2908599 | doi = 10.1016/j.nurt.2010.05.004 }}</ref>

=== Cardiovascular disease ===
Since ] 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, ] is dependent on tetrahydrobiopterin availability.<ref>{{cite journal | vauthors = Channon KM | title = Tetrahydrobiopterin: regulator of endothelial nitric oxide synthase in vascular disease | journal = Trends in Cardiovascular Medicine | volume = 14 | issue = 8 | pages = 323–7 | date = November 2004 | pmid = 15596110 | doi = 10.1016/j.tcm.2004.10.003 }}</ref> Increasing tetrahydrobiopterin in endothelial cells by augmenting the levels of the biosynthetic enzyme GTPCH can maintain endothelial nitric oxide synthase function in experimental models of disease states such as diabetes,<ref>{{cite journal | vauthors = Alp NJ, Mussa S, Khoo J, Cai S, Guzik T, Jefferson A, Goh N, Rockett KA, Channon KM | display-authors = 6 | title = Tetrahydrobiopterin-dependent preservation of nitric oxide-mediated endothelial function in diabetes by targeted transgenic GTP-cyclohydrolase I overexpression | journal = The Journal of Clinical Investigation | volume = 112 | issue = 5 | pages = 725–35 | date = September 2003 | pmid = 12952921 | pmc = 182196 | doi = 10.1172/JCI17786 | author-link5 = Tomasz Guzik }}</ref> atherosclerosis, and hypoxic pulmonary hypertension.<ref>{{cite journal | vauthors = Khoo JP, Zhao L, Alp NJ, Bendall JK, Nicoli T, Rockett K, Wilkins MR, Channon KM | display-authors = 6 | title = Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension | journal = Circulation | volume = 111 | issue = 16 | pages = 2126–33 | date = April 2005 | pmid = 15824200 | doi = 10.1161/01.CIR.0000162470.26840.89 | doi-access = free }}</ref> However, treatment of people with existing coronary artery disease with oral tetrahydrobiopterin is limited by oxidation of tetrahydrobiopterin to the inactive form, ], with little benefit on vascular function.<ref>{{cite journal | vauthors = Cunnington C, Van Assche T, Shirodaria C, Kylintireas I, Lindsay AC, Lee JM, Antoniades C, Margaritis M, Lee R, Cerrato R, Crabtree MJ, Francis JM, Sayeed R, Ratnatunga C, Pillai R, Choudhury RP, Neubauer S, Channon KM | display-authors = 6 | title = Systemic and vascular oxidation limits the efficacy of oral tetrahydrobiopterin treatment in patients with coronary artery disease | journal = Circulation | volume = 125 | issue = 11 | pages = 1356–66 | date = March 2012 | pmid = 22315282 | pmc = 5238935 | doi = 10.1161/CIRCULATIONAHA.111.038919 }}</ref>

=== Neuroprotection in prenatal hypoxia ===
Depletion of tetrahydrobiopterin occurs in the hypoxic brain and leads to toxin production. Preclinical studies in mice reveal that treatment with oral tetrahydrobiopterin therapy mitigates the toxic effects of hypoxia on the developing brain, specifically improving white matter development in hypoxic animals.<ref>{{cite journal | vauthors = Romanowicz J, Leonetti C, Dhari Z, Korotcova L, Ramachandra SD, Saric N, Morton PD, Bansal S, Cheema A, Gallo V, Jonas RA, Ishibashi N | display-authors = 6 | title = Treatment With Tetrahydrobiopterin Improves White Matter Maturation in a Mouse Model for Prenatal Hypoxia in Congenital Heart Disease | journal = Journal of the American Heart Association | volume = 8 | issue = 15 | pages = e012711 | date = August 2019 | pmid = 31331224 | doi = 10.1161/JAHA.119.012711 | pmc = 6761654 | doi-access = free }}</ref>

=== Programmed cell death ===
GTPCH (GCH1) and tetrahydrobiopterin were found to have a secondary role protecting against ] by ] in cellular models by limiting the formation of toxic ] peroxides.<ref>{{cite journal | vauthors = Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, Merl-Pham J, Bao X, Anastasov N, Kössl J, Brandner S, Daniels JD, Schmitt-Kopplin P, Hauck SM, Stockwell BR, Hadian K, Schick JA | display-authors = 6 | title = GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling | journal = ACS Central Science | volume = 6 | issue = 1 | pages = 41–53 | date = January 2020 | pmid = 31989025 | pmc = 6978838 | doi = 10.1021/acscentsci.9b01063 }}</ref> Tetrahydrobiopterin acts as a potent, diffusable ] that resists ]<ref>{{cite journal | vauthors = Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, Molina H, Garcia-Bermudez J, Pratt DA, Birsoy K | display-authors = 6 | title = Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers | journal = Nature Chemical Biology | volume = 16 | issue = 12 | pages = 1351–1360 | date = December 2020 | pmid = 32778843 | pmc = 8299533 | doi = 10.1038/s41589-020-0613-y }}</ref> and enables ] cell survival via promotion of angiogenesis.<ref>{{cite journal | vauthors = Chen L, Zeng X, Wang J, Briggs SS, O'Neill E, Li J, Leek R, Kerr DJ, Harris AL, Cai S | display-authors = 6 | title = Roles of tetrahydrobiopterin in promoting tumor angiogenesis | journal = The American Journal of Pathology | volume = 177 | issue = 5 | pages = 2671–2680 | date = November 2010 | pmid = 20847284 | pmc = 2966821 | doi = 10.2353/ajpath.2010.100025 }}</ref>

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | chapter = Clinical Review Report: Sapropterin dihydrochloride (Kuvan) | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK533813/ | location = Ottawa, Canada | publisher = ] (CADTH) | date = September 2017 | title = CADTH Common Drug Reviews | pmid = 30462435 | id = Bookshelf ID: NBK533813 }}
* {{cite journal | vauthors = Blau N | title = Genetics of Phenylketonuria: Then and Now | journal = Human Mutation | volume = 37 | issue = 6 | pages = 508–15 | date = June 2016 | pmid = 26919687 | doi = 10.1002/humu.22980 | doi-access = free }}
* {{cite journal | vauthors = Dubois EA, Cohen AF | title = Sapropterin | journal = British Journal of Clinical Pharmacology | volume = 69 | issue = 6 | pages = 576–7 | date = June 2010 | pmid = 20565448 | pmc = 2883749 | doi = 10.1111/j.1365-2125.2010.03643.x | doi-access = free }}
* {{cite journal | vauthors = Muntau AC, Adams DJ, Bélanger-Quintana A, Bushueva TV, Cerone R, Chien YH, Chiesa A, Coşkun T, de Las Heras J, Feillet F, Katz R, Lagler F, Piazzon F, Rohr F, van Spronsen FJ, Vargas P, Wilcox G, Bhattacharya K | display-authors = 6 | title = International best practice for the evaluation of responsiveness to sapropterin dihydrochloride in patients with phenylketonuria | journal = Molecular Genetics and Metabolism | volume = 127 | issue = 1 | pages = 1–11 | date = May 2019 | pmid = 31103398 | doi = 10.1016/j.ymgme.2019.04.004 | doi-access = free | hdl = 11336/126862 | hdl-access = free }}
* {{cite journal | vauthors = Qu J, Yang T, Wang E, Li M, Chen C, Ma L, Zhou Y, Cui Y | display-authors = 6 | title = Efficacy and safety of sapropterin dihydrochloride in patients with phenylketonuria: A meta-analysis of randomized controlled trials | journal = British Journal of Clinical Pharmacology | volume = 85 | issue = 5 | pages = 893–899 | date = May 2019 | pmid = 30720885 | pmc = 6475685 | doi = 10.1111/bcp.13886 | doi-access = free }}
* {{cite journal | vauthors = van Wegberg AM, MacDonald A, Ahring K, Bélanger-Quintana A, Blau N, Bosch AM, Burlina A, Campistol J, Feillet F, Giżewska M, Huijbregts SC, Kearney S, Leuzzi V, Maillot F, Muntau AC, van Rijn M, Trefz F, Walter JH, van Spronsen FJ | display-authors = 6 | title = The complete European guidelines on phenylketonuria: diagnosis and treatment | journal = Orphanet Journal of Rare Diseases | volume = 12 | issue = 1 | pages = 162 | date = October 2017 | pmid = 29025426 | pmc = 5639803 | doi = 10.1186/s13023-017-0685-2 | doi-access = free }}
{{refend}}

== External links ==
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/sapropterin | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Sapropterin }}
* {{cite web | url = https://druginfo.nlm.nih.gov/drugportal/name/sapropterin%20dihydrochloride | publisher = U.S. National Library of Medicine | work = Drug Information Portal | title = Sapropterin dihydrochloride }}

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