disorders of purine, pyrimidine and porphyrin metabolism of purine, pyrimidine... · depression of...
TRANSCRIPT
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Disorders of purine, pyrimidine and porphyrin metabolism
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Exam questions
• Disorders of uric acid metabolism
• Disorders of purines/pyrimidines metabolism
• Hepatic and cutaneous porpyhrias
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Nucleic bases
imidazole
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Nukleosides
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Nukleotides
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Inosine!!!!!
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Uridine!!!!!!!
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Role of nucleotides
• Information carriers (DNA/RNA)
• Universal source of energy (ATP 30 kJ/mol)
• Second messengers: cGMP a cAMP
• Coenzymes and group transfer (e.g.AdoMet)
http://www.benbest.com/health/cycAMP.gif
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Cell cycle and P/P synthesis Salvage pathway
De novo biosynthesis
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PRPP = 5-fosforibosylpyrofosfate
• Purines: first step in IMP synthesis
• Pyrimidines: last steps in UMP synthesis
• P/P: salvage pathway
http://ead.univ-angers.fr/~jaspard/Page2/COURS/2N2NH3aaetUree/2Figures/9AAaromatiques/8PRPP.gif
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Synthesis and degradation of P/P
Precursors
Nukleotides (IMP, UMP)
Free bases
Other nucleotides
Degradation products
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Metabolism of purines and pyrimidines
purines pyrimidines
PRPP 1st step Last steps
product IMP UMP
localization cytoplasm cytoplasm + 1 enzyme in mitochondria
Degradation products
Uric acid, ammonia CO2, ammonia, -AIB
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http://arthritis-research.com/content/figures/ar1909-2.gif
purinosome
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http://scienceblogs.com/moleculeoftheday/images/gout-cartoon.jpg
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Uric acid
• Trioxopurine
• Keto/enol
• Physiological pH: monosodium urate
• Limited solubility
• Free radical scaveneger
http://0.tqn.com/d/chemistry/1/0/M/R/1/Uric_acid.jpg
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Urinary concrements-uric acid
http://img.medscape.com/pi/emed/ckb/pediatrics_general/980683-983759-669.jpg
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http://img.medscape.com/slide/migrated/editorial/cmecircle/2006/4933/images/edwards/slide006.gif
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Renal reabsorption and secretion
The uric acid transportasome. Current understanding of uric acid transport in the proximal renal tubule. Monocarboxylates accumulate in the tubular cell through sodium-dependent monocarboxylate transporters SLC5A8 and SLC5A12, and dicarboxylates through SLC13A3. Uric acid enters the cell in exchange for monocarboxylate via apical URAT1 and for dicarboxylate via apical OAT4. Apical SLC2A9v2 plays a significant role in uric acid reabsorption, the reabsorbed uric acid exiting the cell through basolateral SLC2A9v1. For efflux of uric acid into the lumen, MRP4 and a voltage-driven organic anion transporter (vOAT1/NPT1) are candidates. OAT1 and OAT3 are known to transport uric acid, although the direction of transport is not clear.
http://img.medscape.com/article/705/178/705178-fig1.jpg
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Gout
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Adenylosuccinate lyase deficiency
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Facial dysmorfia in ADSL deficiency
Holder-Espinasse M et al. J Med Genet 2002;39:440-442
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ADSL deficiency
• AR inheritance
• SAICAR toxic for neurons (impaired utilization of glucose), S-Ado may be protective
• Uncertain role of purine depletion (not confirmed)
• Variable neurological findings (stereotypic movement, PMR, seizures, hypotonia)
• Facial dysmorphy in some patients
• SAICAR detection in urine by a simple test
• Treatment unknown
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PPRP synthase superactivity
• William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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PPRP synthase superactivity
• X-linked diseases
• Increased activity (activating mutation)
• Hyperuricemia, gout
• Neurological impairment (unclear mechanism)
William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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hypoxanthin
O O
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William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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HGPRT deficiency- diapers
http://newborns.stanford.edu/images/urates2.jpg
http://www.dent.ucla.edu/pic/visitors/teethloss/images/PreFig9.jpg
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Deficit HGPRT-urate tophus
• William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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HGPRT deficiency
http://newborns.stanford.edu/images/urates2.jpg
http://www.dent.ucla.edu/pic/visitors/teethloss/images/PreFig9.jpg
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HGPRT deficiency
• William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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HGPRT deficiency
• William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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HGPRT activity in fibroblasts
• William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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HGPRT deficiency
• X-linked disease
• Various forms: Lesch-Nyhan syndrome, partial deficiency
• Hyperuricemia (the only treatable feature of disease)
• Neurological abnormalities: automutilation, aggresivity, PMR, seizures, gait disturbances
• Various theories for neurological anormalities incl. purines depletion, possibly secondary dopamin synthesis defect (decreased DOPA-decarboxylase)
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hypoxanthin
O O
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http://www.herringlab.com/photos/2/55-2,8-dihydroxyadenine97-P3.jpg
APRT deficiency
• Production of 2,8-dihydroxyadeninu
• Very low solubility: 3 mg/L (vs. uric acid 150 mg/L)
• 2,8-DHA cannot be distinguished from uric acid in routine stone analysis
• Treatment: allopurinol William N Nyhan, Bruce A Barshop, Pinar T Ozand (eds). Atlas of metabolic diseases, 2nd edition. London: Hodder Arnold, 2005
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In type I, the isolated XO deficiency leads to a block in UA production and accumulation of xanthine and hypoxanthine whereas the conversion of allopurinol to oxypurinol is unaffected. In type II the combined deficiency of the XO and AO complex impairs the production of UA and oxypurinol.
Arikyants N. et al. Pediatr Nephrol 2007
Zapůjčeno laskavostí Dr.B.Stibůrkové
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AU
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Minutes
2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00
AU
0.000
0.010
0.020
0.030
0.040
0.050
0.060
0.070
0.080
0.090
Minutes
2.00 3.00 4.00 5.00 6.00 7.00 8.00 9.00 10.00 11.00 12.00 13.00 14.00
xanthine
uric acid
hypoxanthine
xanthine
uric acid
hypoxanthine
control
patient
HPLC chromatogram močových P/P
Zapůjčeno laskavostí Dr.B.Stibůrkové
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Xanthinuria
• Isolated XO deficiency
• Urolithiasis and occasionally myopathy due to xanthin crystalls
• S and U- uric acid decreased!!!!!!
• Treatment: fluid intake
• combined XO/SO deficiency due to Mo cofactor (neurological abnormalities)
http://www.tamilspider.com/attachments/Resources/3322-71129-xanthine.jpg
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Orotic aciduria
• UMP synthase deficiency
• Overproductzio of orotic acid---crystalluria (lithiasis is rare)
• Decreased production of pyrimidines—abnormal hematopoesis-megaloblastic anemia—PMR, FTT
• Treatment: uridine (kinase converts to UMP)
http://www.prohealthdynamics.com/images/orotic_and_sulphuric_acid_ojrx.jpg
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DPD deficiency
• Complete deficiency • Childhood onset
• PMR, hypertonus, autism
• Mikrocephaly, dysmorphy
• No treatment known
• Partial deficiency • % of common population
• Toxicity of 5-fluorouracil (neutropenia,stomatitis, neurological symptoms)
http://www.ijo.in/articles/2008/56/4/images/IndianJOphthalmol_2008_56_4_336_41422_1.jpg
Neurotrophic keratitits
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Thymidine phosphorylase deficiency
OMP
TP
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Mitochondrial neurogastrointestinal encephalopathy syndrome (MNGIE)
• Start in 1st to 5th decade (60% pacientů before 20 y)
• Progressive GIT dysmotility (early satiance, nauzea/vomiting after food ingestion, dysfagia, reflux, diarhoe/obstipation)
• Progressive kachexia
• Neurological abnormalities-demylinization of peripheral nerves, parestesias, hypacusis
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Thymidine phosphorylase deficiency
OMP
TP
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Porphyrias, werewolves and vampires
http://devoid.blogs.heraldtribune.com/files/2009/10/werewolf.jpg
http://th01.deviantart.com/fs21/300W/f/2007/258/a/5/Vampire_Caitlin_Deadly_Beauty_by_VampHunter777.jpg
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Hemoproteins-examples
• Hemoglobine/myoglobine- O2 transport (Fe2+)
• Catalase-conversion of hydrogen peroxide to water and oyygen
• Cytochromes
– Transfer of electrones in respiratory chain
(Fe2+ ↔Fe3+)
– NOS
• Cystathionine beta-synthase-structural role
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Heme-structure
http://www.home-air-purifier-expert.com/images/heme.jpg
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http://www.reactome.org/figures/porphyrin_biosynthesis.jpg
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Porphyrias
• Often AD inheritance, some AR inheritance
• Usual onset in adulthood
• Common manifestation only after exposure (fasting, menses, drugs, sunlight)
• Classification-site of enzyme defect: • Liver
• Erythropoetic
• Classification-symptoms: • Neurovisceral
• Skin
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http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/18/FB/texte_alt_jleejd00203_gr1.jpg
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http://terrycomeau.com/Porphyria/Porphyria.htm http://www.pathguy.com/lectures/erythrodontia.jpg
How to detect porphyria by eye?
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Absorption spectrum of porphyrins
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http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/18/FB/texte_alt_jleejd00203_gr1.jpg
Photosensitivity in porphyrias
• Absorption in UV region
• Production of free radicals
• Development of inflammation (rush at start)
• Blistering and scaring may occurr
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Neurological symptoms in porphyrias • Peripheral NS
• Increased activity of sympathicus: tachycardia, hypertension
• Abdominal pain-nonlocalised but also colic
• Parestesias
• Peripheral neuropathy- muscle weaknes
• Central NS • Aggitation
• Psychotic episodes
• Mechanisms: synaptic function interference (GABA vs.ALA similarity), heme depletion(NOS, Trp pyrrolase)
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Mary Stuart-AIP?
en.wikipedia.org/wiki/Porphyria
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http://terrycomeau.com/Porphyria/Porphyria.htm
Pathogenesis of AIP
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http://terrycomeau.com/Porphyria/Porphyria.htm
Lack of feedback decrease in heme synthesis
Increased heme degradation by HO-1
Increased need of heme synthesis
Increased turnover of xenobiotics
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http://terrycomeau.com/Porphyria/Porphyria.htm
Lack of feedback decrease in heme synthesis
Increased heme degradation by HO-1
Increased need of heme synthesis
Increased turnover of xenobiotics
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http://terrycomeau.com/Porphyria/Porphyria.htm
Lack of feedback decrease in heme synthesis
Increased heme degradation by HO-1
Increased need of heme synthesis
Increased turnover of xenobiotics
Treatment of AIP
1
2 3
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http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/18/FB/texte_alt_jleejd00203_gr1.jpg
PCT (porphyria cutanea tarda)
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http://www.jle.com/en/revues/medecine/ejd/e-docs/00/04/18/FB/texte_alt_jleejd00203_gr1.jpg
CEP(congenital erythropetic porphyria)
http://www.pathguy.com/lectures/erythrodontia.jpg
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Porphyrias
CEP a EP
• Early onset
• Photosensitivity and erythrodontia
• Hemolysis and liver abnormalities- ca hepatis
• Neurological abnormalities rarely
• Therapy:transfusion, depression of hematopoesis by hydroxyurea, transplant
PCT
• Photosensitivity
• No neurological abnormalities
• Secondary origin possible (herbicide in Turkey)
• Treatment: phlebotomy, chlorochine (depletion of porphyrines from liver)
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Pathobiochemistry of fasting
• Fasting – poor
- 3 phasis –
Phase early gluconeogenetic – normoglycaemia
gluconeogenesis from Ala (liver) and Gln (GIT, kidney)
lipolysis – beta oxidation of FFA; ketogenesis
Phase of adaptation – decreased gluconeogenesis
increased beta oxidation FFA; ketogenesis
protein sparing phase
Terminal phase – protein katabolismus
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Ketogenesis
http://www.wikipedia.org
Acute hypoketotic hypoglycaemia
Metabolic acidosis
Hepatopathy
Liver disease (Reye – like)
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Ketolysis
3-oxothiolase deficiency
Defect SCOT
Ketoacidosis
Hyperketotic hypoglycaemia
coma, hypotony
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Thank you