tetrahydrobiopterin

Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency.{{cite web|url=https://rarediseases.org/rare-diseases/tetrahydrobiopterin-deficiency/|title=Tetrahydrobiopterin Deficiency|website=National Organization for Rare Disorders (NORD)|access-date=2017-10-09}} Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures.{{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}} However, most people with PKU have little or no benefit from BH4*2HCL.{{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 }}

The most common adverse effects, 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.{{cite book|title=Austria-Codex|editor=Haberfeld, H|publisher=Österreichischer Apothekerverlag|location=Vienna|date=1 March 2017|language=German|at=Kuvan 100 mg-Tabletten}}

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.

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 monoamine neurotransmitters. 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 It works as a cofactor, being required for an enzyme's activity as a catalyst, mainly hydroxylases.

{{further|Tryptophan hydroxylase}}

Tetrahydrobiopterin is a cofactor for tryptophan hydroxylase (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan (5-HTP).

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

Tyrosine hydroxylase (TH) catalyses the conversion of L-tyrosine to L-DOPA (DOPA), which is the precursor for dopamine. 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;{{cite web|url=http://ghr.nlm.nih.gov/gene/GCH1|title=Genetics Home Reference: GCH1|publisher=National Institutes of Health }} currently, this condition is typically treated with carbidopa/levodopa, which directly restores dopamine levels within the brain.

Nitric oxide synthase (NOS) catalyses the conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide (NO). 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.{{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 }} As a co-factor for nitric oxide synthase, tetrahydrobiopterin supplementation has shown beneficial results for the treatment of endothelial dysfunction in animal experiments and clinical trials, although the tendency of BH4 to become oxidized to BH2 remains a problem.{{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}}

Ether lipid oxidase (alkylglycerol monooxygenase, AGMO) catalyses the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol.

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

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).{{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 }}

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 vitamin C) can reduce BH3 radical into BH4,{{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 }} preventing the BH3 radical from reacting with other free radicals (superoxide and peroxynitrite specifically). Without this recycling process, uncoupling of the endothelial nitric oxide synthase (eNOS) enzyme and reduced bioavailability of the vasodilator nitric oxide occur, creating a form of endothelial dysfunction.{{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 }} Ascorbic acid is oxidized to dehydroascorbic acid 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.{{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 }}

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, depression, 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 ADHD, hypertension, endothelial dysfunction, and chronic kidney disease.{{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 }}{{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}} 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.{{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 }}

In psychiatry, tetrahydrobiopterin has been hypothesized to be involved in the pathophysiology of depression, although evidence is inconclusive to date. 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

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.{{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 }} 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."{{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 }}

Since nitric oxide 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 nitric oxide synthase is dependent on tetrahydrobiopterin availability.{{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 }} 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,{{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 }} atherosclerosis, and hypoxic pulmonary hypertension.{{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 }} However, treatment of people 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.{{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 }}

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.{{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 }}

GTPCH (GCH1) and tetrahydrobiopterin were found to have a secondary role protecting against cell death by ferroptosis in cellular models by limiting the formation of toxic lipid peroxides.{{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 }} Tetrahydrobiopterin acts as a potent, diffusable antioxidant that resists oxidative stress{{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 }} and enables cancer cell survival via promotion of angiogenesis.{{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 }}

{{reflist}}

{{refbegin}}

• {{cite book | chapter = Clinical Review Report: Sapropterin dihydrochloride (Kuvan) | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK533813/ | location = Ottawa, Canada | publisher = Canadian Agency for Drugs and Technologies in Health (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}}

• {{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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