6-Pyruvoyltetrahydropterin synthase deficiency

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6-Pyruvoyltetrahydropterin synthase deficiency
Other namesHyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency [1]
Autosomal recessive - en.svg
This condition is inherited in an autosomal recessive manner

6-Pyruvoyltetrahydropterin synthase deficiency is an autosomal recessive disorder that causes malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency. [2] It is a recessive disorder that is accompanied by hyperphenylalaninemia. Commonly reported symptoms are initial truncal hypotonia, subsequent appendicular hypertonia, bradykinesia, cogwheel rigidity, generalized dystonia, and marked diurnal fluctuation. Other reported clinical features include difficulty in swallowing, oculogyric crises, somnolence, irritability, hyperthermia, and seizures. Chorea, athetosis, hypersalivation, rash with eczema, and sudden death have also been reported. Patients with mild phenotypes may deteriorate if given folate antagonists such as methotrexate, which can interfere with a salvage pathway through which dihydrobiopterin is converted into tetrahydrobiopterin via dihydrofolate reductase. Treatment options include substitution with neurotransmitter precursors (levodopa, 5-hydroxytryptophan), monoamine oxidase inhibitors, and tetrahydrobiopterin. [3] Response to treatment is variable and the long-term and functional outcome is unknown. To provide a basis for improving the understanding of the epidemiology, genotype–phenotype correlation and outcome of these diseases, their impact on the quality of life of patients, and for evaluating diagnostic and therapeutic strategies a patient registry was established by the noncommercial International Working Group on Neurotransmitter Related Disorders (iNTD). [4]

Contents

Presentation

Movement disorders mentioned are caused by the inability to produce L-Dopa. Dopamine is a neurotransmitter which is also involved in movement. The absence of enough of this molecule causes the movement disorders in an affected individual. [5]

Mechanism

To understand how the absence of this enzyme affects the body, we must look at the BH4 synthesis pathway. PTPS is an intermediate in this cycle and is needed to convert 7,8 - dihydroneopterin triphosphate to 6-Pyruvoyltetrahydryobiopterin. 6-Pyruvoyltetrahydryobiopterin is converted into BH4 (Tetrahydrobiopterin), but since it stops at 6-Pyruvoyltetrahydrobiopterin no BH4 is made. [6] The absence of BH4 affects the metabolism of Phenylalanine. This is the reason that PKU and PTPS deficiency share some similar symptoms. However, since BH4 is needed for much more than just the metabolism of Phenylalanine, there are other symptoms as well. [7]

This image depicts the pathway for the synthesis if tetrahydrobiopterin, a very important cofactor in the human body. BH4 synthesis pathway.jpg
This image depicts the pathway for the synthesis if tetrahydrobiopterin, a very important cofactor in the human body.

Structure and function of 6-Pyruvoyltetrahydropterin Synthase

PTPS is a hexamer of identical subunits. The PTPS monomer folds into a sequential four-stranded, antiparallel 𝛃-sheet. Three PTPS monomers form a 12-stranded antiparallel 𝛃-barrel by tight association between the N and C terminus of 2 adjacent subunits. The active enzyme complex is formed by two trimers in a head-to-head fashion. The active site is in between the trimer-trimer interface and has 3 monomers: A, A′, B. [8] There are three histidine residues that form the metal-binding site in the substrate binding pocket: His 23,48 and 50. Residues Cys42, Glu133, and His89 are in close proximity to the binding pocket but are not binding it. These are thought to serve as proton donors and acceptors during catalysis. The cofactor bound can be either Mg2+ or Ni2+ (Protein Database). As previously mentioned it is involved in the biosynthesis of BH4 and catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin synthase. The kinetic values for this enzyme are KM = 8.1 μM and Vmax = 120 nmol/min/mg. [9] The structure of PTPS is unique and is different than other examples of antiparallel 𝛃-barrels. It is described as being formed by "a three-fold symmetrical arrangement of subunits". [8] A similar 𝛃-barrel formation has been discovered in CKS2, [10] the difference between PTPS and CKS2 is that the formation of the latter is metal induced and reversible. The PTPS trimer is similar to a porin [8] and is hypothesized to serve as a tunnel for dihydroneopterin triphosphate.

Diagnosis

PTPS deficiency can usually be detected by the same screening test used for PKU, because both disorders result in elevated levels of Phenylalanine. This test is known as the Guthrie test and is done on babies a few days after birth. Another diagnostic method is to measure Pteridine levels in urine and to measure neurotransmitters 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA). [11]

Treatment

Epidemiology

Taiwanese Chinese are more likely to get PTPS deficiency as the prevalence in Taiwanese Chinese is about 1/132,000 compared to white individuals at about 1/1,000,000. PTPS deficiency occurs most commonly in Asian countries and this makes sense because of the incidence of this disease in Taiwanese Chinese being significantly higher than any other population. [12]

History

PTPS deficiency is not necessarily its own disease. It shares history with PKU and hyperphenylalaninemia (HPA) . Asbjørn Følling, a physician studying metabolic diseases, identified an excess of phenylpyruvate as the cause of a strange, musty odor from the urine of two Norwegian children. [13] Further research by Penrose in 1935 lead to the coining of the term, "phenylketonuria". The foundations for dietary restrictions were laid down by George Jervis and Host Bickel which is still one of the best ways to treat PKU. However, this very practice of excluding phenylalanine from the diet was not working for other forms of HPA. This was attributed to a deficiency of tetrahydrobiopterin (BH4), a cofactor for PAH. [14] The most common form of BH4 deficiency is due to PTPS. Later on PTPS was discovered and it was learned that PKU causes HPA but not all HPA is PKU. [15]

See also

Related Research Articles

<span class="mw-page-title-main">Phenylketonuria</span> Amino acid metabolic disorder

Phenylketonuria (PKU) is an inborn error of metabolism that results in decreased metabolism of the amino acid phenylalanine. Untreated PKU can lead to intellectual disability, seizures, behavioral problems, and mental disorders. It may also result in a musty smell and lighter skin. A baby born to a mother who has poorly treated PKU may have heart problems, a small head, and low birth weight.

<span class="mw-page-title-main">Phenylalanine hydroxylase</span> Mammalian protein found in Homo sapiens

Phenylalanine hydroxylase (PAH) (EC 1.14.16.1) is an enzyme that catalyzes the hydroxylation of the aromatic side-chain of phenylalanine to generate tyrosine. PAH is one of three members of the biopterin-dependent aromatic amino acid hydroxylases, a class of monooxygenase that uses tetrahydrobiopterin (BH4, a pteridine cofactor) and a non-heme iron for catalysis. During the reaction, molecular oxygen is heterolytically cleaved with sequential incorporation of one oxygen atom into BH4 and phenylalanine substrate. In humans, mutations in its encoding gene, PAH, can lead to the metabolic disorder phenylketonuria.

<span class="mw-page-title-main">Tetrahydrobiopterin</span> Chemical compound

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

<span class="mw-page-title-main">Tetrahydrobiopterin deficiency</span> Medical condition

Tetrahydrobiopterin deficiency (THBD, BH4D) is a rare metabolic disorder that increases the blood levels of phenylalanine. Phenylalanine is an amino acid obtained normally through the diet, but can be harmful if excess levels build up, causing intellectual disability and other serious health problems. In healthy individuals, it is metabolised (hydroxylated) into tyrosine, another amino acid, by phenylalanine hydroxylase. However, this enzyme requires tetrahydrobiopterin as a cofactor and thus its deficiency slows phenylalanine metabolism.

<span class="mw-page-title-main">QDPR</span> Human gene

QDPR is a human gene that produces the enzyme quinoid dihydropteridine reductase. This enzyme is part of the pathway that recycles a substance called tetrahydrobiopterin, also known as BH4. Tetrahydrobiopterin works with an enzyme called phenylalanine hydroxylase to process a substance called phenylalanine. Phenylalanine is an amino acid that is obtained through the diet; it is found in all proteins and in some artificial sweeteners. When tetrahydrobiopterin interacts with phenylalanine hydroxylase, tetrahydrobiopterin is altered and must be recycled to a usable form. The regeneration of this substance is critical for the proper processing of several other amino acids in the body. Tetrahydrobiopterin also helps produce certain chemicals in the brain called neurotransmitters, which transmit signals between nerve cells.

<span class="mw-page-title-main">GTP cyclohydrolase I</span>

GTP cyclohydrolase I (GTPCH) (EC 3.5.4.16) 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 (GTP) to form 7,8-dihydroneopterin triphosphate (7,8-DHNP-3'-TP, 7,8-NH2-3'-TP).

<span class="mw-page-title-main">Biopterin</span> Chemical compound

Biopterins are pterin derivatives which function as endogenous enzyme cofactors in many species of animals and in some bacteria and fungi. The prototypical compound of the class is biopterin, as shown in the infobox. Biopterins act as cofactors for aromatic amino acid hydroxylases (AAAH), which are involved in synthesizing a number of neurotransmitters including dopamine, norepinephrine, epinepherine, and serotonin, along with several trace amines. Nitric oxide synthesis also uses biopterin derivatives as cofactors. In humans, tetrahydrobiopterin (BH4) is the endogenous cofactor for AAAH enzymes.

<span class="mw-page-title-main">Sepiapterin reductase</span> Mammalian protein found in Homo sapiens

Sepiapterin reductase is an enzyme that in humans is encoded by the SPR gene.

In enzymology, a 6-pyruvoyltetrahydropterin 2'-reductase (EC 1.1.1.220) is an enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">6-Pyruvoyltetrahydropterin synthase</span> Class of enzymes

The enzyme 6-pyruvoyltetrahydropterin synthase catalyzes the following chemical reaction:

<span class="mw-page-title-main">PTS (gene)</span> Protein-coding gene in the species Homo sapiens

6-pyruvoyltetrahydropterin synthase, also known as PTS, is a human gene which facilitates folate biosynthesis.

<span class="mw-page-title-main">PCBD1</span> Protein-coding gene in the species Homo sapiens

Pterin-4-alpha-carbinolamine dehydratase is an enzyme that in humans is encoded by the PCBD1 gene.

<span class="mw-page-title-main">Hyperphenylalaninemia</span> Medical condition

Hyperphenylalaninemia is a medical condition characterized by mildly or strongly elevated concentrations of the amino acid phenylalanine in the blood. Phenylketonuria (PKU) can result in severe hyperphenylalaninemia. Phenylalanine concentrations are routinely screened in newborns by the neonatal heel prick, which takes a few drops of blood from the heel of the infant. Standard phenylalanine concentrations in unaffected persons are about 2-6mg/dl phenylalanine concentrations in those with untreated hyperphenylalaninemia can be up to 20 mg/dL. Measurable IQ deficits are often detected as phenylalanine levels approach 10 mg/dL. Phenylketonuria (PKU)-like symptoms, including more pronounced developmental defects, skin irritation, and vomiting, may appear when phenylalanine levels are near 20 mg/dL .Hyperphenylalaninemia is a recessive hereditary metabolic disorder that is caused by the body's failure to convert phenylalanine to tyrosine as a result of the entire or partial absence of the enzyme phenylalanine hydroxylase.

7,8-Dihydroneopterin triphosphate (DHNTP) is an intermediate in tetrahydrobiopterin biosynthesis. It is transformed by 6-pyruvoyltetrahydropterin synthase into 6-pyruvoyl-tetrahydropterin. It is also used in the Queuosine/Archeosine Pathway.

<span class="mw-page-title-main">6-carboxytetrahydropterin synthase</span> Enzyme

6-carboxytetrahydropterin synthase (EC 4.1.2.50, CPH4 synthase, queD (gene), ToyB, ykvK (gene)) is an enzyme with systematic name 7,8-dihydroneopterin 3'-triphosphate acetaldehyde-lyase (6-carboxy-5,6,7,8-tetrahydropterin and triphosphate-forming). This enzyme catalyses the following reversible chemical reaction.

Dihydropteridine reductase deficiency (DHPRD) is a genetic disorder affecting the tetrahydrobiopterin (BH4) synthesis pathway, inherited in the autosomal recessive pattern. It is one of the six known disorders causing tetrahydrobiopterin deficiency, and occurs in patients with mutations of the QDPR gene.

Pterin-4 alpha-carbinolamine dehydratase deficiency (PCDD) is one of the known forms of tetrahydrobiopterin deficiency. This condition is associated with mutations of the PCBD1 gene. As of 2020, PCDD was the rarest form of BH4 deficiency in terms of cases described in medical literature.

Autosomal recessive GTP cyclohydrolase I deficiency (AR-GTPCHD) is a disorder associated with the deficient operation of the enzyme GTP cyclohydrolase I. The condition leads to insufficient production of the cofactor tetrahydrobiopterin necessary for the proper synthesis of dopamine and serotonin and for maintenance of adequate levels of phenylalanine. As of 2020, autosomal recessive GTP cyclohydrolase I deficiency was one of the six known causes of tetrahydrobiopterin deficiency. It is also considered part of the spectrum of dopa-responsive dystonias.

Autosomal dominant GTP cyclohydrolase I deficiency (AD-GTPCHD) is a disease caused by dysfunction of GTP cyclohydrolase I, an enzyme that plays an important role in the synthesis of tetrahydrobiopterin, and, as a consequence, of dopamine. This condition is one of the six known causes of tetrahydrobiopterin deficiency and is the most frequently-reported cause of dopa-responsive dystonia.

Mild non-BH4-deficient hyperphenylalaninemia (HPANBH4) is a rare metabolic disorder characterized by mild hyperphenylalaninemia (HPA) and a range of variable neurologic symptoms, including movement abnormalities and intellectual impairment. HPANBH4 has an autosomal-recessive pattern of inheritance.

References

  1. ↑ "Orphanet: 6 pyruvoyl tetrahydropterin synthase deficiency". www.orpha.net. Retrieved 16 June 2019.
  2. ↑ Thöny B; Blau N (1997). "Mutations in the GTP cyclohydrolase I and 6-pyruvoyl-tetrahydropterin synthase genes". Hum. Mutat. 10 (1): 11–20. doi:10.1002/(SICI)1098-1004(1997)10:1<11::AID-HUMU2>3.0.CO;2-P. PMID   9222755. S2CID   9085242.
  3. ↑ Pearl PL; Taylor JL; Trzcinski S; Sokohl A (May 2007). "The pediatric neurotransmitter disorders". J Child Neurol . 22 (5): 606–616. doi:10.1177/0883073807302619. PMID   17690069. S2CID   10689202.
  4. ↑ "Home".
  5. ↑ Ogawa, Atsushi; Kanazawa, Masaki; Takayanagi, Masaki; Kitani, Yutaka; Shintaku, Haruo; Kohno, Yoichi (2008). "A case of 6-pyruvoyl-tetrahydropterin synthase deficiency demonstrates a more significant correlation of l-Dopa dosage with serum prolactin levels than CSF homovanillic acid levels". Brain and Development. 30 (1). Elsevier BV: 82–85. doi:10.1016/j.braindev.2007.05.011. ISSN   0387-7604.
  6. ↑ Escalante-Acosta, Bruno Alfonso; Ramos-Brizuela, Luz Maria; Vargas-Robles, Hilda; Rubio-Guerra, Alberto Francisco (2010-09-29). "Is tetrahydrobiopterin a therapeutic option in diabetic hypertensive patients?". Integrated Blood Pressure Control. 3: 125–32. doi: 10.2147/ibpc.s7479 . PMC   3172060 . PMID   21949628.
  7. ↑ Regier, Debra S; Greene, Carol L (January 5, 2017). "Phenylalanine Hydroxylase Deficiency". University of Washington, Seattle. PMID   20301677 . Retrieved November 27, 2023.
  8. 1 2 3 Nar, H.; Huber, R.; Heizmann, C.W.; Thöny, B.; Bürgisser, D. (March 1994). "Three-dimensional structure of 6-pyruvoyl tetrahydropterin synthase, an enzyme involved in tetrahydrobiopterin biosynthesis". The EMBO Journal. 13 (6): 1255–1262. doi:10.1002/j.1460-2075.1994.tb06377.x. ISSN   0261-4189. PMC   394939 . PMID   8137809.
  9. ↑ Scherer-Oppliger, Tanja; Leimbacher, Walter; Blau, Nenad; Thöny, Beat (1999-10-29). "Serine 19 of Human 6-Pyruvoyltetrahydropterin Synthase Is Phosphorylated by cGMP Protein Kinase II". Journal of Biological Chemistry. 274 (44): 31341–31348. doi: 10.1074/jbc.274.44.31341 . ISSN   0021-9258. PMID   10531334.
  10. ↑ Parge, H.E.; Arvai, A.S.; Tainer, J.A. (1995-02-07). "Human Ckshs2 Atomic Structure: A Role for ITS Hexameric Assembly in Cell Cycle Control". Science. 262 (5132): 387–95. doi:10.2210/pdb1cks/pdb. PMID   8211159.
  11. ↑ "6-pyruvoyl-tetrahydropterin synthase deficiency | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-12-09.
  12. ↑ Liu, Tze-Tze; Chiang, Szu-Hui; Wu, Sheu-Jen; Hsiao, Kwang-Jen (November 2001). "Tetrahydrobiopterin-deficient hyperphenylalaninemia in the Chinese". Clinica Chimica Acta. 313 (1–2): 157–169. doi:10.1016/s0009-8981(01)00669-6. ISSN   0009-8981. PMID   11694255.
  13. ↑ FollingIA. 1934. Uber Ausscheidung von Phenylbrenztraubensaure in den Harn als Stoffwechselanomalie in Verbindung mit Inbicillitat. Hoppe Seylers Z Physiol Chem 227:169.
  14. ↑ Blau N, Thony B, Cotton RGH, Hyland K. 2001. Disorders of tetrahydrobiopterin and related biogenic amines. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Childs B, Vogelstein B, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill. pp 1725–1776.
  15. ↑ Blau, Nenad (February 2016). "Genetics of Phenylketonuria: Then and Now". Human Mutation. 37 (6): 508–515. doi: 10.1002/humu.22980 . PMID   26919687.
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