what is the role of tetrahydrobiopterin

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

Full Answer

What is tetrahydrobiopterin?

Tetrahydrobiopterin (BH4) is a naturally occurring essential cofactor for the conversion of a nitrogen component of l-arginine to NO by endothelial nitric oxide synthase (eNOS).

What is the role of tetrahydrobiopterin in serotonin synthesis?

Tetrahydrobiopterin is essential for serotonin synthesis. Serotonin works in the digestive system and helps prevent dysfunction [ 29 ]. In mice, BH4 supplementation can help bring serotonin levels back to normal and steady digestive function [ 29 ].

What is the role of tetrahydrobiopterin in phenylketonuria?

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 .

What is the role of sapropterin in the treatment of tetrahydrobiopterin deficiency?

Sapropterin is indicated in tetrahydrobiopterin deficiency caused by GTP cyclohydrolase I (GTPCH) deficiency, or 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency. Also, BH4*2HCL is FDA approved for use in phenylketonuria (PKU), along with dietary measures. However, most people with PKU have little or no benefit from BH4*2HCL.

Where is Tetrahydrobiopterin used?

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.

What is the function of tetrahydrobiopterin in the hydroxylation of phenylalanine?

The natural cofactor of phenylalanine hydroxylase (PAH), tetrahydrobiopterin (BH4), regulates the enzyme activity as well as being essential in catalysis.

What does tetrahydrobiopterin deficiency do to the body?

Tetrahydrobiopterin (BH4) deficiency causes the body to build up an abnormally high level of phenylalanine, one of the building blocks of proteins. In addition, BH4 deficiency leads to low levels of certain neurotransmitters, chemical messengers that control many body functions.

How is Tetrahydrobiopterin produced?

Tetrahydrobiopterin (BH4) Metabolism BH4 itself is synthesized in a multistep pathway starting from guanosine triphosphate (GTP) and, when formed, requires several enzymes to maintain it in its active state (Fig. 15-2).

How does tyrosine work?

Tyrosine is in all tissues of the human body and in most of its fluids. It helps the body build proteins in your body, and produce enzymes, thyroid hormones, and the skin pigment melanin. It also helps the body produce neurotransmitters that help nerve cells communicate.

What is the role of phenylalanine hydroxylase?

Normal Function Phenylalanine is found in all proteins and in some artificial sweeteners. Phenylalanine hydroxylase is responsible for the conversion of phenylalanine to another amino acid, tyrosine. The enzyme works with a molecule called tetrahydrobiopterin (BH4) to carry out this chemical reaction.

How can I increase my BH4 level?

Folate enhances the binding of BH4 to NOS through a pteridine-binding domain and then 5-methyltetrahydrofolate facilitates the electron transfer by BH4 from the NOS reductase domain to the heme. Therefore, folic acid (FA) enhances the chemical synthesis and stabilization of BH4 (2).

What does PKU smell like?

Symptoms of PKU Untreated children with phenylketonuria often give off a mousy or musty body odor in their urine and sweat. This odor is the result of phenylacetic acid, which is a by-product of phenylalanine.

What does Hyperphenylalaninemia mean?

Hyperphenylalaninemia is a hereditary metabolic disorder that causes elevated blood phenylalanine (Phe). Hyperphenylalaninemias are classified as Phenylketonuria PKU (Phe > 6 mg/dL) or mild hyperphenylalaninemia (mHPA) (Phe 2–6 mg/dL).

Why do we need tryptophan?

Function. The body uses tryptophan to help make melatonin and serotonin. Melatonin helps regulate the sleep-wake cycle, and serotonin is thought to help regulate appetite, sleep, mood, and pain. The liver can also use tryptophan to produce niacin (vitamin B3), which is needed for energy metabolism and DNA production.

What enzyme converts dopa to dopamine?

aromatic amino acid decarboxylaseDOPA is converted to dopamine by aromatic amino acid decarboxylase. Dopamine-β-hydroxylase hydroxylates dopamine to norepinephrine, which is methylated to epinephrine by phenylethanolamine N-methyltransferase. Tyrosine hydroxylase is the rate-limiting enzyme of the pathway.

Why is phenylalanine converted to tyrosine?

Phenylalanine is an essential amino acid while tyrosine is non-essential. Besides its incorporation into proteins, the only function of phenylalanine is its conversion to tyrosine. For this reason, ingestion of tyrosine can reduce the dietary requirement of phenylalanine.

What is the cofactor of tetrahydrobiopterin?

Tetrahydrobiopterin is a naturally occurring nutrient and an essential co-factor of enzymes involved in the biosynthesis of 5-hydroxytryptamine (5HT, serotonin), dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), melatonin, and nitric oxide [1 ]. The enzymes for which it is a co-factor include tryptophan hydroxylase, phenylalanine hydroxylase, tyrosine hydroxylase, nitric oxide synthase, and glyceryl ether mono-oxygenase.

What is the cofactor of tyrosine hydroxylase?

Tetrahydrobiopterin is an essential cofactor for the neurotransmitter synthesizing enzymes tyrosine hydroxylase ( which catalyzes the conversion of tyrosine to l-dopa) and tryptophan hydroxylase (which catalyzes the conversion of tryptophan to 5-hydroxytryptophan [5-HTP]), as well as for phenylalanine hydroxylase (which converts phenylalanine to tyrosine). BH4 itself is synthesized in a multistep pathway starting from guanosine triphosphate (GTP) and, when formed, requires several enzymes to maintain it in its active state (Fig. 15-2 ).

What is BH4 in vascular disease?

Tetrahydrobiopterin (BH4) is a naturally occurring essential cofactor for the conversion of a nitrogen component of l -arginine to NO by endothelial nitric oxide synthase (eNOS). Investigators report in Arteriosclerosis, Thrombosis & Vascular Biology that unavailability of BH4 results in attenuation of eNOS production of NO, instead generating superoxide. In vascular disease states, there is oxidative degradation of BH4 by ROS. Augmentation of BH4 concentrations in vascular disease by pharmacological supplementation, by enhancement of its rate of biosynthesis, or by measures to reduce its oxidation, have been shown to enhance NO bioavailability. 42

What is BH4?

Tetrahydrobiopterin. Tetrahydrobiopterin (BH4) is the cofactor for phenylalanine hydroxylase. Some mutations for PAH are considered to be relatively milder than others; some studies have shown that certain of these mutations result in enzyme activity that may be improved by the addition of BH4 to the diet.

What is BH4 biosynthesis?

Tetrahydrobiopterin (BH4) is essential for the biosynthesis of dopamine, noradrenaline, and serotonin, which serve as cofactors for tyrosine hydroxylase (TH) and tryptophan hydroxylase. GTP cyclohydrolase (GCH) is the first and rate-limiting enzyme for BH4 biosynthesis. Genetic defects in an allele of the GCH gene can result in dopa-responsive dystonia due to partial BH4 deficiency. To explore the transcriptional control of the GCH gene, we analyzed the signaling pathway. Bacterial lipopolysaccharide (LPS) greatly enhanced the expression of GCH in RAW264 cells, and the induction of GCH by LPS was suppressed by treatment with either a MEK1/2 inhibitor or an inhibitor for the NF-κB pathway. Next, we analyzed two types of biopterin-deficient transgenic mice. We found that both mice exhibited motor disorders with slight differences. Dopamine and TH protein levels were markedly and concurrently increased from birth (P0) to P21 in wild-type mice, and these increases were abolished in both types of biopterin-deficient mice. Our results suggest that the developmental manifestation of psychomotor symptoms in BH4 deficiency might be attributable at least partially to the high dependence of dopaminergic development on the availability of BH4.

Which amino acids are able to transport amino acids into the CNS?

The large neutral amino acids (LNAAs), phenylalanine, tyrosine, tryptophan, and the branched-chain amino acids share the same l -amino acid transport system across the blood–brain barrier. High levels of phenylalanine in the blood, therefore, impede the transport of these other amino acids into the CNS.

Is BH4 a cofactor?

BH 4 is also a required cofactor for the aromatic amino acid hydroxylases (phenyalanine, tyrosine and tryptophan hydroxylases), although for these enzymes it functions as a redox-active cofactor in a manner that is fundamentally different from its mechanism of use by NO synthases.

What does BH4 do to the body?

The depletion of BH4 reduces the synthesis of neurotransmitters like serotonin, melatonin, dopamine, norepinephrine, and epinephrine. These compounds are essential for controlling daily body functions including mood, sleep cycle, memory, and appetite [ 25 ]. Loss of BH4 might explain some of the symptoms of depression.

What is BH4?

Tetrahydrobiopterin (BH4), also known as sapropterin (INN), plays a key role in a number of physiological processes. It is involved in the formation of neurotransmitters, heart and endothelial dysfunction, the immune response, and pain sensitivity [ 1 ]. BH4 is essential for the action of several enzymes, including ones responsible ...

Is BH4 dose dependent?

The effects of oral administration of BH4 are dose-dependent and further studies are required to investigate its long-term effects [ 9 ]. Additionally, the combination of BH4 with other antioxidant compounds is not yet tested [ 11 ].

Is BH4 a biological function?

BH4 is involved in other biological functions; however, no clinical evidence supports the use of supplemental BH4 for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts.

Does tetrahydrobiopterin interact with trimethoprim?

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. A combination of tetrahydrobiopterin with levodopa can lead to increased excitability.

Is BH4 in cerebrospinal fluid lower in autism?

Levels of BH4 in cerebrospinal fluid are 42% lower in children with Autism Spectrum Disorder (ASD) [ 16 ]. It is possible that metabolic pathways that need BH4 are dysfunctional in children with ASD.

Does sapropterin help with phenylketonuria?

It helps with the heart, brain, and the digestive and reproductive systems. A synthetic version called sapropterin can help manage phenylketonuria and is under investigation for its potential in heart disease and autism. Read on to learn how it works.

Which enzyme is responsible for the recovery of BH4 from its reduced form BH2?

QDPR is the enzyme which is typically responsible for the recovery of BH4 from its reduced form BH2. 13 However, studies have also shown that the enzyme DHFR is also able perform this recovery activity. DHFR, like MTHFR, is an enzyme in the one carbon pathway, hence the similarity in their names.

What is BH4 biosynthesis?

BH4 biosynthesis and activity. BH4 as a co-factor. BH4 helps make nitric oxide. BH4 helps make serotonin. BH4 plays a role in producing dopamine. BH4 recovery. BH4 and NOS uncoupling. BH2 is converted back to BH4. BH4 Deficiency and Elevated BH2.

What is the BH4 gene?

BH4 is formed from the abundant , simple molecule GTP in a three-step process, each step catalyzed by a different enzyme; GTP cyclohydrolase I (encoded for by the gene GCH1 ), pyruvoyltetrahydropterin synthase ( PTS) and sepiapterin reductase ( SPR ). 2 Pathological mutations in any of these genes can lead to BH4 deficiency, it is not yet clear if there are polymorphisms that result in milder reductions in function.

Is BH4 a cofactor for NOS?

BH4 and NOS uncoupling. BH2 is an interesting product as it can also function as a cofactor for the various NOS enzymes. However, whereas NOS coupled with BH4 converts arginine into NO, NOS coupled with BH2 promotes the formation of superoxides and hydrogen peroxide, two highly toxic compounds, which are associated with several ...

Is Methf converted to DHF?

However, dietary folate is not the only source of DHF; MeTHF can be used in a reaction to directly form nucleic acids, the building blocks of DNA, rather than being used by MTHFR. When used to make DNA, MeTHF is converted into DHF, and so DHFR also plays a recovery role.

What is the cofactor of tetrahydrobiopterin?

Tetrahydrobiopterin is a naturally occurring nutrient and an essential co-factor of enzymes involved in the biosynthesis of 5-hydroxytryptamine (5HT, serotonin), dopamine, noradrenaline (norepinephrine), adrenaline (epinephrine), melatonin, and nitric oxide [1 ]. The enzymes for which it is a co-factor include tryptophan hydroxylase, phenylalanine hydroxylase, tyrosine hydroxylase, nitric oxide synthase, and glyceryl ether mono-oxygenase.

What is BH4? What are its functions?

Tetrahydrobiopterin (BH4) is a critical cofactor for the nitric oxide synthases. In the absence of BH 4, these enzymes become uncoupled, fail to produce nitric oxide, and begin to produce superoxide and other reactive oxygen species (ROS). BH 4 levels are modulated by a complex biosynthetic pathway, salvage enzymes, and by oxidative degradation. The enzyme GTP cyclohydrolase-1 catalyzes the first step in the de novo synthesis of BH 4 and new evidence shows that this enzyme is regulated by phosphorylation, which reduces its interaction with its feedback regulatory protein (GFRP). In the setting of a variety of common diseases, such as atherosclerosis, hypertension, and diabetes, reactive oxygen species promote oxidation of BH 4 and inhibit expression of the salvage enzyme dihydrofolate reductase (DHFR), promoting accumulation of BH 2 and NOS uncoupling. There is substantial interest in therapeutic approaches to increasing tissue levels of BH 4, largely by oral administration of this agent. BH 4 treatment has proved effective in decreasing atherosclerosis, reducing blood pressure, and preventing complications of diabetes in experimental animals. While these basic studies have been very promising, there are only a few studies showing any effect of BH 4 therapy in humans in treatment of these common problems. Whether BH 4 or related agents will be useful in treatment of human diseases needs additional study.

What is BH4 biosynthesis?

Tetrahydrobiopterin (BH4) is essential for the biosynthesis of dopamine, noradrenaline, and serotonin, which serve as cofactors for tyrosine hydroxylase (TH) and tryptophan hydroxylase. GTP cyclohydrolase (GCH) is the first and rate-limiting enzyme for BH4 biosynthesis. Genetic defects in an allele of the GCH gene can result in dopa-responsive dystonia due to partial BH4 deficiency. To explore the transcriptional control of the GCH gene, we analyzed the signaling pathway. Bacterial lipopolysaccharide (LPS) greatly enhanced the expression of GCH in RAW264 cells, and the induction of GCH by LPS was suppressed by treatment with either a MEK1/2 inhibitor or an inhibitor for the NF-κB pathway. Next, we analyzed two types of biopterin-deficient transgenic mice. We found that both mice exhibited motor disorders with slight differences. Dopamine and TH protein levels were markedly and concurrently increased from birth (P0) to P21 in wild-type mice, and these increases were abolished in both types of biopterin-deficient mice. Our results suggest that the developmental manifestation of psychomotor symptoms in BH4 deficiency might be attributable at least partially to the high dependence of dopaminergic development on the availability of BH4.

What is BPH4 in the brain?

Tetrahydrobiopterin (BPH4), a co-enzyme which catalyses the hydroxylation of phenylalanine to tyrosine in liver and kidney and tyrosine to L-DOPA in the brain , has an important role in the normal functioning of the mammalian brain [72 ]. BPH4 has recently been shown to be a almost as effective as ascorbic acid as an antioxidant in rat brain homogenate and more effective than ascorbic acid as a scavenger of superoxide [ 73 ]. The dipyridyl herbicide, paraquat, is a potent inducer of Parkinson-like syndrome and BPH4 was found to be an effective inhibitor of its activity in cultured hepatocytes [ 73 ]. BPH4 is oxidised to the dihydropterin, BPH2 under these conditions and the antioxidant mechanism is shown in Scheme 5.4.

What amino acids are involved in the transport of phenylalanine?

The large neutral amino acids (LNAAs), phenylalanine, tyrosine, tryptophan, and the branched-chain amino acids share the same l -amino acid transport system across the blood–brain barrier. High levels of phenylalanine in the blood, therefore, impede the transport of these other amino acids into the CNS. Tyrosine and tryptophan are important neurotransmitter precursors; relative deficiency or imbalance of which may contribute to the neuropsychiatric symptoms seen in some adult PKU patients who have resumed an unrestricted diet. Treatment with supplemental LNAAs (in tablet form) theoretically will increase the competition with phenylalanine for transport into the CNS. A net reduction in phenylalanine and an increase in CNS tyrosine and tryptophan may result in improvement in symptoms. Long-term outcome data are not yet available. This treatment is not suitable for children or women in the childbearing years that might be contemplating pregnancy.

What is BH4 used for?

BH4, or tetrahydrobiopterin, is used for many imperative and fundamental processes in the body.

What is BH4?

BH4 is necessary in the production of neurotransmitters like serotonin, melatonin, dopamine, norepinephrine, and epinephrine, which help with body functions such as mood, sleep cycle, memory and appetite . If BH4 is low then it is possible for neurotransmitters to be low.

How long does it take for BH4 to decrease?

R. Ischemia (blood flow restriction, such as a stroke or hypoxia) reduces BH4 in the heart by 85-87% after 30-60 minutes of ischemia. R. Bh4 can help vascular flow, since depletion of BH4 can contribute to post-ischemic eNOS dysfunction.

Does BH4 help with oxidative stress?

Heart disease, high cholesterol, diabetes, high blood pressure and stroke are all associated with high levels of oxidative stress. BH4 may help reduce this oxidative stress and prevent these complications. R.

What Is Tetrahydrobiopterin (Bh4)?

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