Tetrahydrobiopterin
Encyclopedia
Tetrahydrobiopterin or sapropterin (INN
International Nonproprietary Name
An International Nonproprietary Name is the official nonproprietary or generic name given to a pharmaceutical substance, as designated by the World Health Organization...

) is a naturally occurring essential cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

 of the three aromatic amino acid hydroxylase enzymes, used in the degradation of amino acid phenylalanine and in the biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 of the neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

s serotonin
Serotonin
Serotonin or 5-hydroxytryptamine is a monoamine neurotransmitter. Biochemically derived from tryptophan, serotonin is primarily found in the gastrointestinal tract, platelets, and in the central nervous system of animals including humans...

 (5-hydroxytryptamine, 5-HT), melatonin
Melatonin
Melatonin , also known chemically as N-acetyl-5-methoxytryptamine, is a naturally occurring compound found in animals, plants, and microbes...

, dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

, norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 (noradrenaline), epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

 (adrenaline), and is a cofactor for the production of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

 (NO) by the nitric oxide synthases.

History

Tetrahydrobiopterin was discovered to play a role as an enzymatic cofactor. The first enzyme found to use tetrahydrobiopterin is phenylalanine hydroxylase
Phenylalanine hydroxylase
Phenylalanine hydroxylase is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PheOH is one of three members of the pterin-dependent amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin and a non-heme iron for...

 (PAH).

Biosynthesis

Tetrahydrobiopterin is biosynthesized from guanosine triphosphate
Guanosine triphosphate
Guanosine-5'-triphosphate is a purine nucleoside triphosphate. It can act as a substrate for the synthesis of RNA during the transcription process...

 (GTP) by three chemical reactions mediated by the enzymes GTP cyclohydrolase I
GTP cyclohydrolase I
GTP cyclohydrolase I is a member of the GTP cyclohydrolase family of enzymes. GTPCH is part of the folate and biopterin biosynthesis pathways. It is responsible for the hydrolysis of guanosine triphosphate to form 7,8-dihydroneopterin 3'-triphosphate .GTPCH is encoded by the gene GCH1...

 (GTPCH), 6-pyruvoyltetrahydropterin synthase
6-pyruvoyltetrahydropterin synthase
In enzymology, a 6-pyruvoyltetrahydropterin synthase is an enzyme that catalyzes the following chemical reaction:Hence, this enzyme has one substrate, 6-[-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-dihydropterin, and two products, 6-pyruvoyl-5,6,7,8-tetrahydropterin and triphosphate.This enzyme...

 (PTPS), and sepiapterin reductase
Sepiapterin reductase
In enzymology, a sepiapterin reductase is an enzyme that catalyzes the following chemical reaction:Thus, the two substrates of this enzyme are 7,8-dihydrobiopterin and NADP+, whereas its three products are tetrahydrobiopterin or sepiapterin, NADPH, and a single hydrogen ion .This enzyme belongs...

 (SR).

Functions

Tetrahydrobiopterin has the following responsibilities as a cofactor:
  • Tryptophan hydroxylase
    Tryptophan hydroxylase
    Tryptophan hydroxylase is an enzyme involved in the synthesis of the neurotransmitter serotonin. TPH catalyzes the following chemical reactionIt employs one cofactor, iron.- Function :...

     (TPH) for the conversion of L-tryptophan (TRP) to 5-hydroxytryptophan
    5-Hydroxytryptophan
    5-Hydroxytryptophan , also known as oxitriptan , is a naturally occurring amino acid and chemical precursor as well as metabolic intermediate in the biosynthesis of the neurotransmitters serotonin and melatonin from tryptophan....

     (5-HTP)
  • Phenylalanine hydroxylase
    Phenylalanine hydroxylase
    Phenylalanine hydroxylase is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PheOH is one of three members of the pterin-dependent amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin and a non-heme iron for...

     (PAH) for conversion of L-phenylalanine (PHE) to L-tyrosine (TYR)
  • Tyrosine hydroxylase
    Tyrosine hydroxylase
    Tyrosine hydroxylase or tyrosine 3-monooxygenase is the enzyme responsible for catalyzing the conversion of the amino acid L-tyrosine to dihydroxyphenylalanine . It does so using tetrahydrobiopterin as a coenzyme. DOPA is a precursor for dopamine, which, in turn, is a precursor for norepinephrine ...

     (TH) for the conversion of L-tyrosine to L-DOPA (DOPA)
  • Nitric oxide synthase
    Nitric oxide synthase
    Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...

     (NOS) for conversion of a guanidino nitrogen of L-arginine (L-Arg) to nitric oxide
    Nitric oxide
    Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

     (NO)
  • Alkylglycerol monooxygenase (AGMO) for the conversion of 1-alkyl-sn-glycerol to 1-hydroxyalkyl-sn-glycerol


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, the body's primary neurotransmitters). Due to its role in the conversion of L-tyrosine in to L-dopa, which is the precursor for dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

. A deficiency in tetrahydrobiopterin can cause severe neurological issues unrelated to a toxic buildup of L-phenylalanine; dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...

 is a vital neurotransmitter
Neurotransmitter
Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse. Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to...

, and is the precursor of norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...

 and epinephrine
Epinephrine
Epinephrine is a hormone and a neurotransmitter. It increases heart rate, constricts blood vessels, dilates air passages and participates in the fight-or-flight response of the sympathetic nervous system. In chemical terms, adrenaline is one of a group of monoamines called the catecholamines...

. 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
Dopamine-responsive dystonia
Dopamine-responsive dystonia , also known as hereditary progressive dystonia with diurnal fluctuation, Segawa's disease, or Segawa's dystonia, is a genetic movement disorder which usually manifests itself during early childhood at around ages 5–8 years .Characteristic symptoms are increased muscle...

; currently, this condition is typically treated with carbidopa/levodopa
Carbidopa/levodopa
Carbidopa/levodopa is the combination of carbidopa and levodopa and is used to treat Parkinson's disease and dopamine-responsive dystonia . It is sold under several brand names, including Sinemet, Parcopa, and Atamet...

, which directly restores dopamine levels within the brain.

BH4 also serves as a catalyst for the production of nitric oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

. Among other things, nitric oxide is involved in vasodilation
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...

, 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.

Phenylketonuria

A deficit in tetrahydrobiopterin biosynthesis
Biosynthesis
Biosynthesis is an enzyme-catalyzed process in cells of living organisms by which substrates are converted to more complex products. The biosynthesis process often consists of several enzymatic steps in which the product of one step is used as substrate in the following step...

 and/or regeneration can result in phenylketonuria
Phenylketonuria
Phenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase , rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine...

 (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
Brain damage
"Brain damage" or "brain injury" is the destruction or degeneration of brain cells. Brain injuries occur due to a wide range of internal and external factors...

, including symptoms of mental retardation
Mental retardation
Mental retardation is a generalized disorder appearing before adulthood, characterized by significantly impaired cognitive functioning and deficits in two or more adaptive behaviors...

, microcephaly
Microcephaly
Microcephaly is a neurodevelopmental disorder in which the circumference of the head is more than two standard deviations smaller than average for the person's age and sex. Microcephaly may be congenital or it may develop in the first few years of life...

, speech impediments such as stuttering
Stuttering
Stuttering , also known as stammering , is a speech disorder in which the flow of speech is disrupted by involuntary repetitions and prolongations of sounds, syllables, words or phrases, and involuntary silent pauses or blocks in which the stutterer is unable to produce sounds...

, slurring, and lisp
Lisp
A lisp is a speech impediment, historically also known as sigmatism. Stereotypically, people with a lisp are unable to pronounce sibilants , and replace them with interdentals , though there are actually several kinds of lisp...

s, seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...

s or convulsion
Convulsion
A convulsion is a medical condition where body muscles contract and relax rapidly and repeatedly, resulting in an uncontrolled shaking of the body. Because a convulsion is often a symptom of an epileptic seizure, the term convulsion is sometimes used as a synonym for seizure...

s, and behavioral abnormalities, among other effects.

Tetrahydrobiopterin, developed by BioMarin under the brand name Kuvan and approved by the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 (U.S.) Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) on December 13, 2007 and European Medicines Agency
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...

 (EMA) in 2008, is a synthetic preparation of the dihydrochloride salt of the substance containing ascorbic acid
Ascorbic acid
Ascorbic acid is a naturally occurring organic compound with antioxidant properties. It is a white solid, but impure samples can appear yellowish. It dissolves well in water to give mildly acidic solutions. Ascorbic acid is one form of vitamin C. The name is derived from a- and scorbutus , the...

, used in the treatment of PKU and tetrahydrobiopterin deficiencies. Sapropterin is the first non-dietary treatment for patients with PKU that has been shown in randomized, double-blind trials to be effective in lowering blood phenylalanine levels.

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. 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, atherosclerosis, and hypoxic pulmonary hypertension.

Tetrahydrobiopterin may be of benefit in the management and treatment of intractable diastolic heart failure, based on research in mice. There are fewer ways to manage systolic heart failure than for diastolic heart failure.

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
Autism
Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. These signs all begin before a child is three years old. Autism affects information processing in the brain by altering how nerve cells and their...

, ADHD, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

, endothelial dysfunction
Endothelial dysfunction
Endothelial dysfunction is a systemic pathological state of the endothelium and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by the endothelium...

, and chronic kidney disease. , no results are available. 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.

Adverse effects

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

Interactions

No interaction studies have been conducted. Because of its mechanism, tetrahydrobiopterin might interact with dihydrofolate reductase inhibitor
Dihydrofolate reductase inhibitor
A dihydrofolate reductase inhibitor is a molecule that inhibits the function of dihydrofolate reductase, and is a type of antifolate.Since folate is needed by rapidly dividing cells to make thymine, this effect may be used to therapeutic advantage. For example, methotrexate is used as cancer...

s like methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 and trimethoprim
Trimethoprim
Trimethoprim is a bacteriostatic antibiotic mainly used in the prophylaxis and treatment of urinary tract infections.It belongs to the class of chemotherapeutic agents known as dihydrofolate reductase inhibitors...

, and NO-enhancing drugs like nitroglycerin, molsidomine
Molsidomine
Molsidomine is an orally active, long acting vasodilating drug. Molsidomine is metabolized in the liver to the active metabolite SIN-1. SIN-1 is an unstable compound that releases nitric oxide upon decay as the actual vasodilating compound.- Chemistry :...

, minoxidil
Minoxidil
Minoxidil is an antihypertensive vasodilator medication which also slows or stops hair loss and promotes hair regrowth. Now off-patent, it is available over-the-counter for the treatment of androgenic alopecia. Minoxidil must be used indefinitely for continued support of existing hair follicles and...

, and PDE5 inhibitors. Combination of tetrahydrobiopterin with levodopa
Levodopa
L-DOPA is a chemical that is made and used as part of the normal biology of some animals and plants. Some animals including humans make it via biosynthesis from the amino acid L-tyrosine. L-DOPA is the precursor to the neurotransmitters dopamine, norepinephrine , and epinephrine collectively...

 can lead to increased excitability.

See also

  • Tetrahydrobiopterin deficiency
    Tetrahydrobiopterin deficiency
    Tetrahydrobiopterin deficiency , also called THB or BH4 deficiency, is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained through the diet. It is found in all proteins and in some artificial sweeteners...

     (THBD, BH4D)
  • Phenylketonuria
    Phenylketonuria
    Phenylketonuria is an autosomal recessive metabolic genetic disorder characterized by a mutation in the gene for the hepatic enzyme phenylalanine hydroxylase , rendering it nonfunctional. This enzyme is necessary to metabolize the amino acid phenylalanine to the amino acid tyrosine...

    (PKU)

External links

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