MUDr. Dana Maňasková


Vyhledávání na medicinman.cz
 

nemoci-sympt/METABOLISMUS/downuv-syndrom/snizene

14-3-3 protein gamma isoform

  • Snížené
  • 14-3-3 proteins are ubiquitous set of chaperone molecules
  • Involved in the elaborate regulation of some fundamental cellular activities and differentiation of neurones
  • Perform this function by binding to intracellular signalling proteins involved in fundamental neurodevelopmental decisions
    • From early stages of neurogenesis to later stages of neural network formation and adult plasticity (Skoulakis and Davis 1998; Ostrerova et al. 1999)
  • Reduced levels of these proteins may thus impact on neurogenesis
    • High level of expression is expected during development (Watanabe et al. 1993)
  • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

AMK snížené

  • Lower plasma levels of free histidine, lysine, tyrosine, phenylalanine, leucine, isoleucine and tryptophan
  • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    • ATP

    Abeta precursor-like protein-1







    Acetylcholine

    • Lower In DS brain supporting the relationship of pathology between DS and AD
    • 1999, Kishnani et al started to treat adult DS patients with cholinesterase inhibitor (Donepezil)
      • Showed the improvement of cognition and life quality in DS patients with dementia
    • Low cholinergic neuron in DS brain might be a cause of cognitive dysfunction in DS
    • 2004, Kishnani et al started to treat DS children with Donepezil and Rivastigmine
      • Some patients showed improvement of language ability, memory, and attention
    • www.clinicaltrials.gov/ct2/show/NCT00748007

    Actin-binding proteins

    • Actin filaments work in networks or bundles that function to control cell shape, distribution of membrane proteins and cell–cell interactions.
    • Actin-binding proteins effect nucleation of actin subunits to induce polymerization as well as cross-linking of actin filaments.
    • A number of actin-binding proteins have been shown to be decreased in fetal DS brain
      • Underpinning that loss of actin function
        • Accounts for dendritic and migration abnormalities

    Drebrin, an actin-binding and -bundling protein

    • Forms dendritic spines
    • Noted to be missing (Weitzdoerfer et al. 2001a)
    • Drebrin displaces tropomyosin from actin filaments
      • Thereby maintaining the actin filaments in a dynamic state suitable for neuronal migration or neuritic outgrowth (Ishikawa et al. 1994)
    • As drebrin is located specifically in dendritic spines
      • Thus synaptically associated
    • Reduction can lead to spine abnormalities
      • Eventually alter the course of synaptic plasticity

    Moesin

    • A protein crucial in controlling axonal growth cone elongation and neuronal polarity
    • Also decreased manifold (Lubec et al. 2001a)
    • Paucity of other actin-binding proteins, including
    • Are involved in actin filament cross-linking, nucleation and capping, has been described (Weitzdoerfer et al. 2002)
    • Findings strongly suggest that the cytoskeletal system is the major cellular component that is severely disrupted by the disease process.
    • Because cytoskeletal regulation is important for
      • Synapse development,
    • Deregulation seems to be a major determinant for migration and synaptic abnormalities associated with DS
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Alpha SNAP and septins


    Beta-Tubulin


    Reduced brain volume

    • Takže porucha dělení buněk / neurogeneze - lze dávat stimulanty a nerové růstové faktory...

    CoQ10

    Collagen VI (alpha 1) chain

    • Snížení protein Engidawork et al. (2001a)
    • Chain precursor protein is decreased in fetal DS brain (Engidawork et al. 2001a)
    • Collagens are members of the substrate adhesion molecule family of morphoregulatory molecules
      • Can function as integrin ligands
    • Activation of integrins can lead to rapid changes in cell adhesion properties in the local microenvironment
      • Can trigger intracellular signalling cascades modulated by extracellular ligands, such as
        • Growth factors
        • Neurotransmitters
    • Integrin receptors therefore provide the developing neural cells with a system capable of linking adhesion/migration information with other development signals controlling proliferation and differentiation (Arenander and De Vellis 1994)
    • Down-regulation of collagen type (VI) alpha 1 chain precursor
      • May therefore contribute to abnormal neuronal migration, at least in part
        • Through its interaction with the integrin family of proteins
    • Reduced expression of collagen type (VI) alpha1 chain precursor
      • Complements the finding of deteriorated expression of axonal guidance proteins
        • Including dihydropyrimidinase-related proteins in fetal DS brain (Weitzdoerfer et al. 2001b).
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Complex IV was found to be significantly inhibited in DS cells.

    • Inhibition of CBS by aminooxyacetate (AOAA), which interferes with the pyridoxal phosphate in the catalytic site,
      • Restored Complex IV activity and ameliorated mitochondrial electron transport and cell proliferation !!!
    • Similar effects were also obtained by CBS normalization by siRNA (Panagaki et al., 2019).

    Dyneins

    • Appear to be responsible for retrograde axonal transport and slow axonal transport
    • Motor function is activated by the dynactin complex (King and Schroer 2000)
    • Components of the dynactin complex, such as
      • Centractin alpha
      • F-actin capping protein subunits
    • Are significantly reduced in fetal DS brain (Gulesserian et al. 2002)
      • Indicating disruption of a supply line that provides structural and functional materials required for normal growth to intraneuronal sites.


    Epigenetická regulace

    • Aberrant expression of splicing, RNA stabilizing and translation factors has been noted in fetal DS brain
    • Failure of the transcription and translation machinery early in life
      • May be responsible for, or may reflect, impaired brain development and deficient wiring of the brain in DS.
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Glutathione

    Glycerophosphoethanolamines

    • Reduced levels

    Glycerophospholipid metabolism

    • Reduced were observed in DS (Yu et al., 2018).

    Glycine and glutamate


    Glycine

    • Může ukazovat na vyšší konzumpci glycinu na syntezu glutathionu (???)

    Growth hormone

    • Deficiency in Down's syndrome children
    • častější nález
    • Domnívám se, že mikroencefalopatie, která je součástí toho, může zhoršovat demenci a že růstový horomon může pomoct i růstu mozku nejen kostry...
    • pubmed.ncbi.nlm.nih.gov/1533556/
    • Some children with Down's syndrome (DS) have growth retardation secondary to growth hormone (GH) deficiency
    • Hypothalamic dysfunction as cause for GH deficiency and growth retardation
      • Hypothalamic-pituitary responses of serum GH concentrations to
        • Levodopa
        • Clonidine
        • Growth-hormone-releasing hormone (GHRH)

    14 prepubertal children with DS

    • Levodopa and clonidine were given, and blood was drawn for determining serum GH levels
      • Delta serum GH during levodopa was
        • 5.7 +/- 6.3 ng ml-1 in DS
        • 13.1 +/- 9.8 ng ml-1 in controls
      • Delta serum GH during clonidine administration was
        • 3.0 +/- 3.2 ng ml-1 in DS
        • 17.3 +/- 5.6 ng ml-1 in controls
      • Children with DS had a significantly lower response to levodopa and clonidine, compared with controls

    Growth-hormone-releasing hormone was given at 1 microgram kg-1 i.v. bolus

    • Bloods for GH were drawn at-15, 0, 15, 30, 60, 90 and 120 min in 14 subjects with DS and 24 normal controls, both groups prepubertal
      • Mean delta serum GH concentration
        • 53.6 +/- 38.3 ng ml-1 in DS
        • 35.6 +/- 25.1 ng ml-1 in controls
      • P < 0.23 non-significant by the Mann-Whitney U-test.
    • Levodopa and clonidine (drugs stimulating hypothalamic GHRH release and secondary pituitary GH release in normal individuals)
      • Do not stimulate GH release in DS.
    • Normal GH response to GHRH in DS indicates normal pituitary function (normal somatotroph response to GHRH) and supports hypothalamic dysfunction in DS.
    • pubmed.ncbi.nlm.nih.gov/9004111/


    Histidine, lysine, tyrosine, phenylalanine, leucine, isoleucine, and tryptophan

    • Reduced levels
    • Tady se jim to ale trochu mlátí - co tedy ten phenylalanin ???
    • Vyjde to u každého nebo v různých studiích jinak ? = Takže vyšetřit v nějaké biochemické poradně jak je to u konrétního dítěte s "fenylketonurií"
      • Ta umí mozek a jeho rozvoj zničit dostatečně sama o sobě

    Homocysteine

    IQ in people with DS

    • Usually falls in the moderately to severely retarded range (IQ = 25–55)
    • Mental age is rarely over 8 years (See Rachidi and Lopes, 2008; Dierssen, 2012)
    • The IQ in DS is not constant during life
      • Decreases with age
    • Early deceleration occurs between the age of 6 months and 2 years
      • With a further decline in adolescents
    • Children with DS exhibit incomplete and delayed acquisition of
      • Motor, linguistic, cognitive, and adaptive functions
    • The brain of a child with DS develops differently
      • Reduced in size
      • Altered in shape
    • Widespread neurogenesis impairment has been documented in fetuses with DS (Contestabile et al., 2007; Guidi et al., 2008, 2011) and in mouse models of DS (Chakrabarti et al., 2007; Bianchi et al., 2010a,b; Trazzi et al., 2011)
      • During critical brain developmental stages
      • One of the major determinants of ID in DS !!!
    • www.frontiersin.org/articles/10.3389/fnbeh.2015.00265/full [2015]

    Interferon gamma (IFNg) production


    JunD component of the AP-1 transcription factors

    Enzymes of Krebs cycle


    Leucine

    Myelinizace


    Nerve growth factor (NGF)

    • Metabolic pathway is altered:
      • Downregulating tissue plasminogen activator (tPA) that activates plasminogen to plasmin, an enzyme converting proNGF to mature NGF;
      • Overexpression of metalloproteinase 9 (MMP-9) further degrades NGF, lowering the amount of mature NGF
    • EGCG inhibits MMP-9, thus protecting NGF
    • Urokinase (uPA) and tPA are activators of plasminogen
      • UPA is inhibited by EGCG, but tPA is not inhibited


    Neuroroliferation impairment



    Nucleoside diphosphate kinase (NDK)-B

    • Snížené
    • NDKs are essential oligomeric enzymes
    • Catalyse the transfer of a phosphate from a nucleoside triphosphate to a nucleoside diphosphate
      • Via the formation of an enzymatic intermediate phosphorylated on a catalytic histidine residue
    • Play a key role in maintenance of the intracellular pool of all dNTPs and NTPs
      • Endows them with a regulatory role in activation of the classical signalling proteins, G-proteins
    • NDK-B has been identified as a transcription factor for the c-myc gene (Postel et al. 1993)
    • Loss of NDK-B will therefore have wide ranging effects involved in
      • Signal transduction
      • Control of gene expression, of developmental genetics and cellular biochemistry
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Deficits in the OXPHOS system at multiple levels such

    • Complex I activity,
    • The ATP synthase
    • The ADP/ATP translocator
    • Adenylate kinase enzyme
    • Ultimately leading to significant energy deficit and increased ROS production in mitochondria (Valenti et al., 2010, 2011)
    • A severe bioenergetic deficit was also found in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice
    • Reduced OXPHOS rate in DS could be associated with impairment of mitochondrial biogenesis, as observed in NPCs (Valenti et al., 2016), and in skin fibroblasts (Piccoli et al., 2013)
    • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

    Rab GDP-dissociation inhibitor (GDI)-beta

    • Snížené
    • GTPases of the Rab family represent important components of the membrane transport machinery
    • GDIs play an important role in regulating their GTP/GDP cycle
      • As well as their subcellular localization
    • Deficient GDI-beta
      • Might lead to vesicular transport defects, as release of Rabs from membranes is compromised,
        • This may interfere with the release of neurotransmitters
          • Thereby underlying mental retardation

    Repressor element-silencing transcription factor (REST) - neurone restrictive silencer factor

    • At the mRNA level snížený
    • Important role in brain development, neuronal plasticity and synapse formation
    • Down-regulated in neurospheres derived from fetal DS (Bahn et al. 2002)
    • Bahn et al. (2002) reported inhibition of REST-regulated genes
      • Theoretically should have been up-regulated, as they are no longer repressed by REST
      • May serve as examples of how post-transcriptional/translational modification affects gene expression
      • Possible that different subtypes of transcription factors differentially regulate gene expression
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    proteins SNX27

    • Abnormally low levels in cells
    • This protein protects neurons from excess quantities of neurotransmitter glutamate.
    • Increased production of miRNA-155, linked to the triplication of several genes on Hsa21, is correlated with a reduced amount of SNX27.
    • Mice genetically modified to produce fewer proteins SNX27 (mice named SNX27+/-)
      • Learning and memory handicap associated with reduced synaptic recycling of glutamate in spite of a globally normal neuroanatomy.
    • www.aimspress.com/article/doi/10.3934/Neuroscience.2020012?viewType=HTML

    Serine

    • Decreased concentration of serine at any age
      • serin se dá suplementovat podobně jako u ALS

    Serotonin, gamma-aminobutyric acid, taurine, and dopamine

    Signalling adapter proteins

    • Snížené
    • Receptor for activated C kinase (RACK)-1,
    • Crk,
    • Crk-like protein
    • Nck adapter protein 2 (Freidl et al. 2001; Weitzdoerfer et al. 2001c; Peyril et al. 2002; Lubec G. unpublished data)
    • RACKs are members of a new group of proteins adapters in different systems.
    • RACK-1 is a 36-kDa protein with seven WD repeats
      • Adapter or scaffold motif
      • Specifically binds with the C2 domain of protein kinase Cbeta (Mochly Rosen et al. 1991)
      • Interact with
        • Integrin beta subunit (Liliental and Chang 1998)
        • Cyclic AMP-specific phophodiesterase isoforms
      • Recruit other proteins to a signalling complex (Yarwood et al. 1999)
    • Decreased expression of RACK-1 in fetal DS brain
      • Can thus limit formation of such signalling complexes
    • Signalling adapter proteins containing Src homology (SH)2 and SH3 domains
      • Such as Crk and Nck adapter protein 2
      • Form multiprotein signalling complexes by recruiting
        • proline-rich motifs through their SH3 domain
        • Phosphorylated tyrosine residues via the SH2 domain
    • Bind to a plethora of effector molecules - their importance in regulating
    • Involved in a host of cellular processes, including
      • Axon guidance,
      • Vesicle motility,
      • Stress response
      • Cytoskeletal reorganization (Buday 1999)
    • Reduced expression of such an adapter molecule reasonably explains
      • Cell proliferation, differentiation and migration abnormalities described in DS brain.
    • onlinelibrary.wiley.com/doi/full/10.1046/j.1471-4159.2003.01614.x

    Sphingosine derivatives - long chain bases (LCBs),

    • Reduced levels
    • Seem to be responsible for nuclear membrane alterations
      • Associated with accelerated aging process in DS.
    • Result from increased conversion to ceramide
      • Due to the activity of ceramide synthase (Hwang et al., 2019).

    Spine density reduction

    Synaptosome-associated protein (SNAP)-25


    Tetrahydrobiopterin

    Down's syndrome


    Thyroid dysfunction

    • Most frequent endocrine abnormality in subjects with DS
    • Prevalence varying between 0 - 66 %
      • Depending on variations in population size, age, laboratory assays or definitions
    • Hypothyroidism is the most frequent thyroid abnormality in DS
      • Congenital in infants with DS of 1:141 live births
        • X incidence ranging between 1:2,500 and <1:5,000 among newborns without DS
    • Hypothyroidism characteristic of early infancy in DS usually presents as a subclinical disorder
    • Distribution of the disorder in this initial stage is similar between sexes
    • Oxidative stress in both hypothyroidism and hyperthyroidism are scarce and controversial
    • Metabolic suppression brought about by the decrease in thyroid hormone levels
    • Some studies reporting an increased oxidative stress in patients with hyperthyroidism as well as with hypothyroidism
    • Thyroid hormone (T3 ) has been shown to downregulate the expression of SOD1
    • Progressive hypothyroidism
      • Leads to an increase in SOD1 activity in the brain of rats
    • Signs and symptoms of hypothyroidism can be difficult to discriminate from DS itself
      • Overlapped to some extent in both DS and hypothyroidism
        • Hypotonia,
        • Lethargy,
        • Mental retardation,
        • Growth failure,
        • Prolonged neonatal jaundice,
        • Delayed closure of fontanelles,
        • Macroglossia,
        • Obesity, etc.
    • Dyrk1A could affect early thyroid morphogenesis through the up-regulation of transcription factors (Nkx2–1, Foxe1, and Pax8) relevant for this embryonic process.
      • Consequently, Dyrk1A-overexpressing mice show significantly thicker but less functional thyroids
        • As shown by the lower T4 hormone excretion
        • Tendency to have increased plasma TSH (Kariyawasam et al., 2015)
    • www.frontiersin.org/articles/10.3389/fnins.2020.00670/full

    Tryptophan, tyrosine, leucine and thiamine


    Tyrosine

    Decrease of tyrosine in DS

    • Compared with controls
    • Decreased tyrosine levels (not significant) with a ratio DS/control = 0.87
      • Which was near the 2:3 ratio
    • Tyrosine is a precursor of thyroid hormones
      • Level is often decreased in DS
    • Would be interesting to test the hypothesis of a correlation between tyrosine and thyroid hormones in subjects with DS
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC5813015/

    Screening metabolomu DS pacientů

    Další rozdíly:

    -

    .metabolicke-zmeny.jpg

    • DS subjects with IQ over 40 vs. IQ under/= 40
    • Did not identify any metabolites with statistically significant concentration differences between the two groups

    Calcium, selenium and zinc


    Ratio of cholesterol to

    • To phospholipid concentration,
    • To phosphatidylcholine,
    • To phosphatidylethanolamine levels
    • All reduced in DS frontal cortex (Yu et al., 2018).
      • Result from an impaired endocannabinoid signaling pathway in DS (Yu et al., 2018).

    Creatinine clearance

    • Is reportedly lower in Downs subjects
    • Reduced glomerular nitration rate
      • Could be causing a distortion in the results
    • Creatinine clearance has a positive linear correlation with both neopterin and biopterin
      • So any reduction in the baseline will be compensated for by reduced pterin excretion
      • This would also account for the elevated levels of biopterins in the plasma of such subjects
    • publications.fondationlejeune.org/article.asp?filename=fjl404.xml

    Defective mitochondrial biogenesis


    Dendritic hypotrophy


    DS and epilepsy: a nutritional connection?

    Esenciální AMK

    48 older healthy DS persons without signs of dementia (?? asi bez Alzheimerovy demence)


    Fosfolipidy

    • Glycerophosphoethanolamines
      • Reduced levels
    • Glycerophospholipid metabolism reduced in DS (Yu et al., 2018).
    • All reduced in DS frontal cortex (Yu et al., 2018):
      • Ratio of cholesterol to phospholipid concentration
      • Phosphatidylcholine,
      • Phosphatidylethanolamine
    • Alterations were suggested to result from an impaired endocannabinoid signaling pathway in DS (Yu et al., 2018)
    • Sphingosine derivatives called long chain bases (LCBs)
      • Hwang et al. (2019) in DS fibroblast reduced
      • Nuclear membrane alterations associated with accelerated aging process in DS
      • Lower LCBs result from increased conversion to ceramide due to the activity of ceramide synthase (Hwang et al., 2019).

    Snížené zpětné vychytávání glutamátu do buněk (asi i na synapsích)

    • Decrease of systemic glutamate uptake
      • By measuring glutamate uptake in platelets and fibroblasts from DS persons (Begni et al., 2003)
    • The authors suggest the use of this peripheral model as a biochemical ex vivo marker of a central glutamatergic dysfunction.
    • Excessive glutamatergic stimulation
      • As a consequence of glutamate uptake deficits could be responsible for neuronal suffering
        • Excitoxicity
        • Cell death
        • May play a key role in the pathophysiology of neuropsychiatric disorders (review: Van der Heijden et al., 2004).
    • www.ncbi.nlm.nih.gov/pmc/articles/PMC2794348/
    • = zákaz čehokoliv s glutamátem, aspartamem, nadbytku vápníku který nejde do kostí (vitamín K bude dobrý)
    • Ale trochu se to tříská ty teorie - jedni píší moc gaba tlumení a málo vzruchu, jide jako tady se mluví i excitotxicitě
      • Je potřeba to nějak dohledat... možná to hlavní bude deficit monoaminů... (?)


    Immune dysfunction and SOD

    • Abnormal metabolism of reactive oxygen species
      • May also contribute to the defective immunity in DS
    • Increase in SOD activity can reduce immunity in DS by:
      • Hyperactive SOD system is likely to result in a decrease in the concentration of superoxide radicals
        • Which may in turn cause a reduction in the microbicidal activity of leukocytes
        • May lead toan excess of hydrogen peroxide which may damage immune cells and impair phagocyte activation
          • Neutrophils from individuals with DS produce less superoxide radicals
          • Two-fold over-production of SOD by intraperitoneal macrophages from transgenic mice
            • Inhibition of extracellular release of superoxide radicals
            • Increased intracellular production of hydrogen peroxide
            • Reduction in microbicidal and fungicidal activity
    • Activityof SOD in the thymus of transgenic mice is increased by two-to five-fold
      • Thymus is more susceptible to lipopolysaccharide-induced apoptotic cell death
    • Increased SOD activity was also associated with an increased production of hydrogen peroxide and lipid peroxidation
      • Addition of tumour necrosis factor
        • Bone marrow cells from thetransgenic mice produced two to three times fewer granulocyte and macrophage colonies than control mice
    • onlinelibrary.wiley.com/doi/pdf/10.1111/j.1469-8749.2000.tb00072.x
    • Potlačit SOD
    • Zvýšit glutathion
    • Dostatek selenu a mědi ve správném poměru
    • Obecně dodat hojně antioxidantů


    Impairment of the methyl cycle


    Impairment of mitochondrial biogenesis

    • Reduced OXPHOS rate in DS could be associated
      • As observed in NPCs (Valenti et al., 2016)
      • In skin fibroblasts DS (Piccoli et al., 2013).
    • Result of
      • Reduced mtDNA content
      • Reduced levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha)
      • Nuclear respiratory factor 1 (NRF-1)
      • mitochondrial transcription factor A (TFAM) (Valenti et al., 2016).
    • Several bioactive compounds display protective effects on mitochondrial signaling pathways, mitochondrial biogenesis, and respiration (Valenti et al., 2018).
    • Likely to be promising therapeutic strategies to ameliorate DS pathological phenotypes (Valenti et al., 2018).
    • Recent studies show the protective effect of:
      • Epigallocatechin gallate (EGCG)
        • Major catechin in green tea
        • Induce neuronal plasticity (Martinez Cue and Dierssen, 2020)
        • And mitochondrial function (Valenti et al., 2016)
        • Leading to cognitive rehabilitation in young adult DS (De La Torre et al., 2016).

    Defects of mitochondrial biogenesis

    • Reduced mtDNA content
    • Reduced levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha)
    • Nuclear respiratory factor 1 (NRF-1)
    • mitochondrial transcription factor A (TFAM) (Valenti et al., 2016).

    Post-exercise resynthesis kinetics of phosphocreatine

    • Is suppressed (Phillips et al. 2013)
      • Bioenergetic mechanisms are impaired in the skeletal muscle of DS

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

    Tetrahydrobiopterin (BH4)

    • 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
      • Mood, sleep cycle, memory and appetite
    • Natural cofactor of the hydroxylases of aromatic aminoacids

    Essential for the activity of various enzymes, including:

    • 4 aromatic amino acid hydroxylases
      • phenylalanine (Phe) hydroxylase - phenylalanine 4-hydroxylase (PAH)
        • PAH converts phenylalanine (PHE) to tyrosine (TYR)
          • Hydroxylated by tyrosine 3-monooxygenase to L-3,4-dihydroxyphenylalanine - a precursor of dopamine
      • Tyrosine 3-monooxygenase
      • tryptophan 5-hydroxylase
      • Alkylglycerol monooxygenase
    • Three NOS (NO synthases) isoenzymes
      • NOS produces nitric oxide (NO) by converting L-arginine to L-citrulline.

    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 6-(D-erythro-1',2',3'-trihydroxypropyl)-pterin

    • Biosynthetic precusor of tetrahydrobiopterin
    • Concentrations are immune activation marker
      • Elevated in patients and to be of diagnostic value
    • Neopterin is primarily produced and released from activated
      • Human monocyte-derived macrophages,
      • Dendritic cells
      • Astrocytes
    • Formation of increased amounts of neopterin in macrophages
      • Mainly initiated by Th1-type cytokine interferon-gamma (IFN-gamma)
      • Type I interferons are also potent inducers of neopterin production in other cells like
        • Dendritic cells or astrocytes
    • Central enzyme involved in the biosynthesis of neopterin is GTP-cyclohydrolase-1 (GCH-1)
      • Converts guanosine triphosphate (GTP) to 7,8-dihydroneopterintriphosphate
    • Monocytic cells enzyme GCH-1
      • Responsible for the production of neopterin
      • Also induces the synthesis of 5,6,7,8-tetrahydrobiopterin (BH4)

    IFN gamma

    • Most important inducer of the antiproliferative and immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO)
      • IDO converts L-tryptophan (TRP) to kynurenine (KYN)
      • First and rate-limiting step of tryptophan catabolism
    • IDO enzyme activity can be calculated - KYN to TRP quotient
    • Accelerated TRP breakdown and elevated KYN/TRP concentrations
      • In many diseases
      • Closely correlate with concentrations of immune activation markers like neopterin
      • Inflammation-activated IDO is driving the TRP catabolism
    • In many cases TRP breakdown rate correlates with neopterin concentrations, extent and the activity of the disease
      • Viral infections or malignant tumors

    Biopterin

    • Appear in urine

    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

    An alternative or salvage pathway involves

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

    Cofactor regeneration requires

    • 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

    Subdivisions of Tetrahydrobiopterin Deficiency

    • In most of these disorders, there are abnormally high levels of the amino acid phenylalanine (hyperphenylalaninemia).
    • Most of these disorders also cause abnormally low levels of neurotransmitters.
    • Progressive neurological abnormalities,
    • Lack of muscle tone (hypotonia),
    • Overproduction of saliva (hypersalivation),
    • Loss of coordination,
    • Abnormal movements, and/or delayed motor development.
    • Prompt diagnosis and treatment of these disorders can prevent potentially severe, irreversible neurological damage.
    .bh4-deficit.jpg

    6-pyruvoyl tetrahydropterin synthase (PTPS) deficiency - porucha 2. kroku syntézy de novo

    Dihydropteridine reductase (DHPR) deficiency - porucha salvage syntézy

    Autosomal recessive guanosine triphosphate cyclohydrolase I (GTPCH) deficiency - porucha 1. kroku syntézy de novo

    Pterin-4alpha-carbinolamine dehydratase (PCD) deficiency - porucha regenerace kofaktoru



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Poslední aktualizace: 30. 9. 2024 22:17:17