MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

Tetrahydrobiopterin

Tetrahydrobiopterin (BH4) - (6R-L-erythro-5,6,7,8-tetrahydrobiopterin)

  • BH4 is present in probably every cell or tissue of higher organisms
  • Plays a key role in a number of biological processes and pathological states associated with
    • Monoamine neurotransmitter formation
    • Cardiovascular and endothelial dysfunction
    • Immune response
    • Pain sensitivity
  • Natural cofactor of the hydroxylases of aromatic aminoacids

Essential for the activity of various enzymes, including:

  • 4 aromatic amino acid hydroxylases
  • Alkylglycerol mono-oxygenase
  • Three NOS (NO synthase) isoenzymes

Tetrahydrobiopterin is the cofactor for the hydroxylation of:

Essential for the production of.

Phenylketonuria (PKU) patients

  • Chronically exposed to high Phe levels
  • High urinary excretion of BH4 metabolites neopterin and biopterin is observed

BH4 levels are maintained in vivo

  • De novo biosynthesis from its precursor guanosine triphosphate
    • Via dihydroneopterin triphosphate
  • Salvage of quinonoid dihydrobiopterin
    • Formed from BH4 during its cofactor role
    • By dihydropteridine reductase
  • Central role in neurotransmitter biosynthesis
  • Disturbances in BH4 metabolism can have severe neurological consequences
  • Exemplified by malignant hyperphenylalaninaemia
    • Genetic disorder of biopterin metabolism
    • BH4 is much reduced

Ageing

  • CSF biopterin levels
    • Decrease with age suggesting that BH4 metabolism is altered in the CNS in normal aging

Alzh. demence

  • Reduced
    • SDAT BH4 levels in serum and CSF
    • BH4 biosynthesis in the temporal lobe
  • Diminished cofactor availability resulting in reduced noradrenalin levels in the CNS
    • May be a contributing factor in the pathogenesis of SDAT

Down's syndrome

  • Develp changes of Alzheimer's disease
  • X noradrenergic system has been suggested in Down's syndrome
  • Altered brain biopterin metabolism in. aging, SDAT and Down's syndrome

Neopterin

  • Biosynthetic precusor of tetrahydrobiopterin

Biopterin

  • Appear in urine

6-Biopterin (L-Biopterin)

  • A pterin derivative, is a NO synthase cofactor.

Folates

  • Not increase tetrahydrobiopterin biosynthesis in the rat as previously thought

Methotrexate

  • Reduce liver biopterin levels
  • Increas urinary biopterin levels in the rat
  • Reduced brain pterin levels but had no influence on liver pterin

BH4 is formed de novo

  • From GTP
  • Via a sequence of three enzymatic steps carried out by
    • GTP cyclohydrolase I
      • Major controlling point
    • 6-pyruvoyltetrahydropterin synthase
    • Sepiapterin reductase

Salvage pathway

  • Converts sepiapterin to biopterin

An alternative or salvage pathway involves

  • Dihydrofolate reductase
    • May play an essential role in peripheral tissues

Cofactor regeneration requires

  • BH4 is the principal active cofactor, and a recycling pathway converts BH2 to BH4
  • Pterin-4a-carbinolamine dehydratase
  • Dihydropteridine reductase
    • Except for NOSs
      • BH4 cofactor undergoes a one-electron redox cycle without the need for additional regeneration enzymes
  • BH4 biosynthesis is controlled in mammals by hormones and cytokines.

BH4 deficiency

  • Due to autosomal recessive mutations in all enzymes
    • Except for sepiapterin reductase
  • Described as a cause of hyperphenylalaninaemia
  • Major contributor to vascular dysfunction associated with hypertension, ischaemic reperfusion injury, diabetes and others
    • Appears to be an effect of oxidized BH4
      • Leads to an increased formation of oxygen-derived radicals instead of NO by decoupled NOS
  • Furthermore, several neurological diseases have been suggested to be a consequence of restricted cofactor availability
    • Oral cofactor replacement therapy to stabilize mutant phenylalanine hydroxylase in the BH4-responsive type of hyperphenylalaninaemia
      • Has an advantageous effect on pathological phenylalanine levels in patients
  • portlandpress.com/biochemj/article-abstract/438/3/397/45633/Tetrahydrobiopterin-biochemistry-and?redirectedFrom=fulltext

Tetrahydrobiopterin (BH4) functions

  • As a H-donor cofactor of aromatic amino acid hydroxylases (Nagatsu et al., 1972; Kaufman and Fisher, 1974)
    • Rate-limiting enzymes for producing monoamine neurotransmitters in the sympathetic nervous system
  • Becomes converted to quinonoid dihydrobioptrin (q-BH2)
    • Through 4alpha-carbinolamine in the process
  • Regeneration of BH4 from q-BH2 by dihydropteridine reductase (DHPR; NADH: quinonoid dihydropteridine oxidoreductase [EC 1. 6. 99. 7]) with NADH
    • Allows this cofactor to function catalytically
  • Biosynthesis of BH4 from GTP by three enzymes (Katoh and Akino, 1986)
    • GTP cyclohydrolase I (Hatakeyama et al., 1989)
    • 6-pyruvoyltetrahydropterin synthase (Inoue et al., 1991)
    • Sepiapterin reductase (SPR) (Sueoka and Katoh, 1982)
  • The BH4-recy-cling by DHPR
    • Is important to control the concentration of the cofactor in the cell
    • DHPR reduces with NADH various quinonoid dihydropterins derived from BH4 and other tetrahydropterins such as
      • 6-methyl tetrahydropterin (6M-PH4)
    • Transient activation of DHPR by
      • M-calpain, a widely distributed Ca2+-activated protease, in vitro.
  • 2.full

4a-hydroxytetrahydrobiopterin dehydratase

  • Reaction: 4a-hydroxytetrahydrobiopterin = 6,7-dihydrobiopterin + H2O
  • 4a-hydroxytetrahydrobiopterin = 6-[(1R,2S)-1,2-dihydroxypropyl]-5,6,7,8-tetrahydro-4a-hydroxypterin
  • 6,7-dihydrobiopterin = 6-[(1R,2S)-1,2-dihydroxypropyl]-6,7-dihydropterin
  • Other name(s): 4alpha-hydroxy-tetrahydropterin dehydratase; 4a-carbinolamine dehydratase; pterin-4alpha-carbinolamine dehydratase; 4a-hydroxytetrahydrobiopterin hydro-lyase
  • Systematic name: a-hydroxytetrahydrobiopterin hydro-lyase (6,7-dihydrobiopterin-forming)
  • In concert with EC 1.5.1.34, 6,7-dihydropteridine reductase, the enzyme recycles 4a-hydroxytetrahydrobiopterin back to tetrahydrobiopterin, a cosubstrate for several enzymes, including aromatic amino acid hydroxylases.
  • The enzyme is bifunctional
    • Also acts as a dimerization cofactor of hepatocyte nuclear factor-1alpha (HNF-1).
  • www.qmul.ac.uk/sbcs/iubmb/enzyme/EC4/2/1/96.html




6-methyltetrahydropterin (6-MPH4)

  • Synthetic analogue
  • Lowers plasma phenylalanine concentrations to the therapeutic range
  • Effective dose of BH4 varies
    • From 1 to 2 mg kg-1 daily in patients with defective biopterin synthesis
    • To 5 mg kg-1 or more in patients with dihydropteridine reductase (DHPR) deficiency
  • The cost of 2 mg kg-1 day-1 of BH4 is comparable to the cost of a low phenylalanine diet.
  • Higher doses of pterins given orally (20 mg kg-1)
    • Raise the levels of tetrahydropterin in cerebrospinal fluid (CSF) to normal
      • In patients with defective biopterin synthesis in whom initial concentration of biopterin species are low
  • In some, but not all, such patients pterin therapy also raises CSF amine metabolite concentrations and ameliorates symptoms.
  • High dose therapy does not appear to be effective in raising CSF pterin levels in patients with DHPR deficiency who already accumulate dihydrobiopterin (BH2) in CSF.
  • Central folate deficiency
    • Is an additional cause of neurological deterioration in patients with DHPR deficiency who require supplementation with folate as folinic acid.
    • It is suggested that the accumulation of BH2 in such patients competitively interferes with folate metabolism.
  • onlinelibrary.wiley.com/doi/abs/10.1007/BF01800658?sid=nlm%3Apubmed

6-pyruvoyltetrahydropterin synthase

  • Reaction: 7,8-dihydroneopterin 3'-triphosphate = 6-pyruvoyl-5,6,7,8-tetrahydropterin + triphosphate
  • 7,8-dihydroneopterin 3'-triphosphate = 6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-dihydropterin
  • Other name(s): 2-amino-4-oxo-6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-dihydroxypteridine triphosphate lyase; 6-[(1S,2R)-1,2-dihydroxy-3-triphosphooxypropyl]-7,8-dihydroxypteridin triphosphate-lyase (6-pyruvoyl-5,6,7,8-tetrahydropterin-forming)
  • Systematic name: 7,8-dihydroneopterin 3'-triphosphate triphosphate-lyase (6-pyruvoyl-5,6,7,8-tetrahydropterin-forming)
  • Catalyses triphosphate elimination and an intramolecular redox reaction in the presence of Mg2+.
  • It has been identified in human liver.
  • This enzyme is involved in the de novo synthesis of tetrahydrobiopterin from GTP, with the other enzymes involved being EC 1.1.1.153 (sepiapterin reductase) and EC 3.5.4.16 (GTP cyclohydrolase I)
  • www.qmul.ac.uk/sbcs/iubmb/enzyme/EC4/2/3/12.html

6,7-dihydropteridine reductase

  • Reaction: a 5,6,7,8-tetrahydropteridine + NAD(P)+ = a 6,7-dihydropteridine + NAD(P)H + H+
  • Other name(s): 6,7-dihydropteridine:NAD(P)H oxidoreductase; DHPR; NAD(P)H2:6,7-dihydropteridine oxidoreductase; NADH-dihydropteridine reductase; NADPH-dihydropteridine reductase; NADPH-specific dihydropteridine reductase; dihydropteridine (reduced nicotinamide adenine dinucleotide) reductase; dihydropteridine reductase; dihydropteridine reductase (NADH); 5,6,7,8-tetrahydropteridine:NAD(P)H+ oxidoreductase
  • Systematic name: 5,6,7,8-tetrahydropteridine:NAD(P)+ oxidoreductase
  • Substrate is the quinonoid form of dihydropteridine
  • Not identical with EC 1.5.1.3 dihydrofolate reductase
  • www.qmul.ac.uk/sbcs/iubmb/enzyme/EC1/5/1/34.html


BH4

  • Infarct size was significantly smaller in the rats (50 ± 2%) and pigs (54 ± 5%) given l-arginine + BH4 in comparison with the vehicle groups (rats 65 ± 3% and pigs 86 ± 5%, P < 0.05).
  • Neither l-arginine nor BH4 alone significantly reduced infarct size.
  • Myocardial BH4 levels were 3.5- to 5-fold higher in pigs given l-arginine + BH4 and BH4 alone.
  • The generation of superoxide in the ischemic-reperfused myocardium was reduced in pigs treated with intracoronary l-arginine + BH4 versus the vehicle group (P < 0.05).
  • Administration of l-arginine + BH4 before reperfusion protects the heart from ischemia–reperfusion injury.
  • The cardioprotective effect is mediated via NOS-dependent pathway resulting in diminished superoxide generation.

Biopterin alpha-D-glucoside



Biopterin - 2-Amino-6-(1,2-dihydroxypropyl)-4(1H)-pteridinone


Downregulation of CR6 interacting factor 1 (CRIF1)

  • Induce mitochondrial dysfunction
    • Resulting in reduced activity of endothelial nitric oxide synthase (eNOS) and NO production in endothelial cells
  • Tetrahydrobiopterin (BH4) is an important cofactor in regulating the balance between NO (eNOS coupling) and superoxide production (eNOS uncoupling)
  • CRIF1 deficiency
    • Increased eNOS uncoupling
    • Depleted levels of total biopterin and BH4
      • By reducing the enzymes of BH4 biosynthesis (GCH-1, PTS, SPR, and DHFR) in vivo and vitro
  • Supplementation of CRIF1-deficient cells with BH4
    • Significantly increased the recovery of Akt and eNOS phosphorylation and NO synthesis
  • Scavenging ROS with MitoTEMPO treatment
    • Replenished BH4 levels by elevating levels of GCH-1, PTS, and SPR
      • But with no effect on the level of DHFR
  • Downregulation of DHFR synthesis regulators p16 or p21 in CRIF1-deficient cells
    • Partially recovered the DHFR expression
  • www.nature.com/articles/s41598-020-57673-9
  • CR6 interacting factor 1 (CRIF1)
    • One of the largest mitoribosomal subunits
    • Essential for the synthesis and insertion of oxidative phosphorylation polypeptides (OXPHOS) in the mitochondrial membrane
  • Lack of CRIF1
    • Major factor underlying misfolded mitochondrial OXPOS subunits
    • Production of excessive mitochondrial ROS in vascular endothelial cells
      • Stimulates endothelial dysfunction via the inactivation of eNOS and decreased NO production
    • mitochondrial ROS that has been linked to mitochondrial dysfunction also mediates the initiation of eNOS uncoupling
  • CRIF1 deficiency limited the common substrate L-arginine to NO synthesis and resulted in eNOS uncoupling.

DHFR deficiency


Deficiency

GTP cyclohydrolase I

  • Dominant form of GTP cyclohydrolase I deficiency results in biopterin deficiency/insufficiency only in the brain

6-pyruvoyl tetrahydropterin synthase

Sepiapterin reductase


Dihydropteridine reductase (DHPR)

  • Can be identified in newborns by an elevated phenylalanine
  • Also require folinic acid supplements

Pterin-4alpha-carbinolamine dehydratase

  • Relatively benign
  • Associated with transient hyperphenylalaninaemia

Diagnosis relies on:

  • Pterin metabolites in urine
  • Dihydropteridine reductase in blood spots
  • Neurotransmitters and pterins in the CSF
  • Demonstration of reduced enzyme activity (red blood cells or fibroblasts)
  • Causative mutations in the relative genes

BH4 deficiency is no longer malignant if therapy:

Single-gene defects affecting the gene GCH1

  • Block the first step in biopterin synthesis lead to

Dopamine-responsive dystonia - Segawa's syndrome

  • Due to the role of BH4 in synthesising neurotransmitters
    • Including Dopamine
  • Treated with supplementation with levodopa
    • Does not require BH4 for conversion to dopamine
  • GCH1 defects
    • Autosomal dominant
      • One defective gene copy is required for the condition to occur
  • en.wikipedia.org/wiki/Biopterin

Malárie

  • BH4 depletion in P. berghei infection may compromise both nitric oxide synthesis and phenylalanine metabolism
  • phenylalanine-metabolism-in-a-murine-model-of-severe">www.severemalaria.org/tetrahydrobiopterin-supplementation-improves-phenylalanine-metabolism-in-a-murine-model-of-severe

Methotrexate - DHFR inhibition

  • Knockdown of DHFR expression both result in significantly reduced levels of BH4 relative to BH2
  • DHFR inhibition does not alter total cellular biopterin concentrations
  • Reduction in the ratio of BH4 to BH2 is sufficient to increase superoxide production and inhibit L-arginine to L-citrulline conversion, a measure of coupled NOS activity
  • link.springer.com/article/10.1007/s11897-012-0097-5

phenylalanine 4-monooxygenase - phenylalaninase; phenylalanine 4-hydroxylase; phenylalanine hydroxylase - PAH

  • L-phenylalanine,tetrahydropteridine:oxygen oxidoreductase (4-hydroxylating)
  • Reaction: L-phenylalanine + a 5,6,7,8-tetrahydropteridine + O2 = L-tyrosine + a 4a-hydroxy-5,6,7,8-tetrahydropteridine
  • The active centre contains mononuclear iron(II).
  • The reaction involves an arene oxide that rearranges to give the phenolic hydroxy group.
  • This results in the hydrogen at C-4 migrating to C-3 and in part being retained.
  • This process is known as the NIH-shift.
  • The 4a-hydroxytetrahydropteridine formed can dehydrate to 6,7-dihydropteridine, both spontaneously and by the action of EC 4.2.1.96, 4a-hydroxytetrahydrobiopterin dehydratase.
  • The 6,7-dihydropteridine must be enzymically reduced back to tetrahydropteridine,
  • By EC 1.5.1.34, 6,7-dihydropteridine reductase, before it slowly rearranges into the more stable but inactive compound 7,8-dihydropteridine.

Plicní hypertenze

  • L-arginine (LA) and tetrahydrobiopterin (BH4) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH4 decrease pulmonary artery pressure (PAP).
  • A combined administration of both may have synergistic effects in the therapy of PAH.
  • Administration of LA alone
    • Restore vascular endothelial NO production
    • Decrease PAP in rodents and in humans
  • ENOS activity highly depends on the intracellular presence of tetrahydrobiopterin (BH4)
  • Binding of BH4 to eNOS
    • Increases stability of the active eNOS dimer
    • Significantly increases enzymatic turnover of LA
  • BH4 deficiency leads to
    • Uncoupling of the dimeric eNOS molecule
    • Enhances generation of superoxide anion
      • Reacts with and neutralizes NO before it is able to accomplish its vasodilatory effects.

Asymmetric dimethylarginine (ADMA)

  • Is a methylated LA
  • Independent risk factor for cardiovascular mortality
  • Inhibits eNOS function and mediates vasoconstriction
  • Patients with high ADMA levels LA supplementation was necessary to enhance statin-mediated eNOS function
  • Human cohort of PAH patients
    • ADMA levels were reduced after oral administration of a phosphodiesterase-5 inhibitor

Prochloraz fungicide

  • On neopterin and biopterin concentrations in blood plasma of common carp
    • [Petr Maršálek, Ivana Mikuliková, Helena Modrá, Zdeňka Svobodová]
  • Neopterin and biopterin are often used as markers of cell mediated immunity.
  • Prochloraz is a widely used imidazole fungicide in horticulture and agriculture
  • 60 juvenile common carp were divided into four groups
    • 15 fish and exposed to prochloraz at concentrations of 0, 50, 150 and 380 mcg·l-1 28 days
  • Concentrations of neopterin (25 ± 7.6 nmol·l-1) and biopterin (190 ± 29 nmol·l-1) in plasma
    • Untreated common carp were comparable with those in mammals
  • Neopterin concentrations significantly (P < 0.01) increased after exposure to prochloraz
    • In comparison to non-exposed fish
  • Biopterin concentrations were not influenced by exposure to prochloraz
  • actavet.vfu.cz/83/2/0101/

Sapropterin Dihydrochloride - 6R-BH4

Klinická studie na endotelovou dysfunkci

  • Sapropterin Dihydrochloride 5 mg/kg twice a day administered as whole tablets orally within 1 hour after morning and evening meals for 13 days and the last dose within 1 hour after a morning meal on Day 14 and Day 28.

Sepiapterin reductase (L-erythro-7,8-dihydrobiopterin forming) - L-erythro-7,8-dihydrobiopterin:NADP+ oxidoreductase

  • Reaction: (1) L-erythro-7,8-dihydrobiopterin + NADP+ = sepiapterin + NADPH + H+ (2) L-erythro-tetrahydrobiopterin + 2 NADP+ = 6-pyruvoyl-5,6,7,8-tetrahydropterin + 2 NADPH + 2 H+
  • Sepiapterin = 2-amino-6-lactoyl-7,8-dihydropteridin-4(3H)-one
  • Tetrahydrobiopterin = 5,6,7,8-tetrahydrobiopterin = 2-amino-6-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydropteridin-4(3H)-one
  • Enzyme catalyses the final step in the de novo synthesis of tetrahydrobiopterin from GTP
  • Found in higher animals and some fungi and bacteria
  • Produces the erythro form of tetrahydrobiopterin
    • EC 1.1.1.325, sepiapterin reductase (L-threo-7,8-dihydrobiopterin forming).
  • www.qmul.ac.uk/sbcs/iubmb/enzyme/EC1/1/1/153.html

Tetrahydrobiopterin

  • Tetrahydrobiopterin is biosynthesized from guanosine triphosphate (GTP)
    • By three chemical reactions mediated by the enzymes
      • GTP cyclohydrolase I (GTPCH),
      • 6-pyruvoyltetrahydropterin synthase (PTPS),
      • Sepiapterin reductase (SR)
  • BH4 can be oxidized by one or two electron reactions, to generate BH4 or BH3 radical and BH2
  • ascorbic acid - vitamin C can reduce BH3 radical into BH4
    • Preventing the BH3 radical from reacting with other free radicals (superoxide and peroxynitrite)
    • Ascorbic acid is oxidized to dehydroascorbic acid during this process, can be recycled back

Sapropterin dihydrochloride (BH4*2HCL)

  • Tablet - approved for use in the United States as a tablet in December 2007
  • Powder in December 2013.[12][11] It was approved for
  • Use in the European Union in December 2008
  • Canada in April 2010
  • Japan in July 2008

Kuvan and Biopten

  • Typical cost of treating a patient with Kuvan is US$100,000 per year
  • BioMarin holds the patent for Kuvan until at least 2024
  • Par Pharmaceutical has a right to produce a generic version by 2020
  • Sapropterin is indicated in tetrahydrobiopterin deficiency caused by:
    • GTP cyclohydrolase I (GTPCH) deficiency,
    • 6-pyruvoyltetrahydropterin synthase (PTPS) deficiency


  • Oxidized form of biopterin is excreted much more rapidly than BH4 (Hoshiga et al., 1993).
  • Gamma-interferon and other cytokines
    • Increase biopterin production by inducing GTP cyclohydrolase 1 (Thöny et al., 2000)
  • Glucocorticoids
    • Prevent cytokine-mediated induction of GTP cyclohydrolase 1 (Simmons et al., 1996), apparently via a cyclic adenosine monophosphate (cAMP)–-mediated signaling cascade (Ohtsuki et al., 2002)
  • Food deprivation of animals
    • Increases biopterin production and concentration in the blood (Koller et al., 1990).
  • Inflammation and infection
    • Tend to depress availability of biopterin in tissues, such as
      • Endothelia of small blood vessels
    • Due to rapid oxidation of the reduced form (McNeill and Channon, 2012).
  • BH4 is converted to the quinoid form of BH2 (qBH2)
    • And must be converted back to BH4 via a salvage pathway

O úroveň výše

Poslední aktualizace: 26. 6. 2021 22:18:46