Porfyriny, lucov barviva, Hb Porphyrins, bile pigments, Hb

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Porfyriny, lucová barviva, HbPorphyrins, bile
pigments, Hb

• Prof. Dr. V. Pelouch, CSc.

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Syntéza porfyrinu a Hb

• Synthesis of porphyrins and Hb

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Syntéza Hb Synthesis of Hb

• Zacíná v mitochochondrii kondensací sukcinylKoA
  (z KC) a glycinu ? NÁSLEDUJE dekarbo-xylace a
  tvorba d- aminolevulinatu
• 2 d aminolevulinate
• prechází do cytosolu ? tvorí se
  porfobilinogen

• First reaction in mitochondriaconden-sation of
  succinylCoA (from KC) and glycine ? NEXT REACTION
  de-carboxylation and formation of d-
  aminole-vulinate
• 2 d aminolevulinate
• is transfered into cytosol ? formed
  porfobilino-
• gene

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Dalí reakce Next reactions

• 4 porfobilinogen ? linear tetrapyrrol ?
  urophorfylinogen ? cophroporfylinogen (cytosol) ?
  in mito-chondria protopor-fylinogen ?
  protopho-fylin ? incorporation of Fe ? Hb
• Side chains A (acetyl) are changed by
  decarbo-xylation to M (metyl) and P (propionyl)
  by decarb. and dehydrogenation to V (vinyl)

• 4 porfobilinogen ? lineární tetrapyrol ?
  uroporfylinogen ? coproporfylinogen (cytosol) ?
  in mito-chondria protopor-fylinogen ?
  proto-porfylin ? incorpo-race Fe ? Hb
• Postranní retezce A (acetyl) se dekarboxylací
  mení na M (metyl), P (propionyl) dekarbox. a
  dehydrogen. na V (vinyl)

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Heme biosynthesis

• Almost 85 of heme biosynthesis occurs in the
  bone marrow,
• much smaller percentage in liver.
• Both the mitochondria and cytoplasm are involved
  in this pathway

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Degradace porfyrinu

• Degradation of porphyrins

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DEGRADATION of Hb

• Globin is removed,
• red heme is degradated in endoplasmic reticulum
  (liver, spleen, bone marrow) by NADPH oxygenase
• biliverdin and bilirubin are produced
• Transport of bilirubin (in binding to albumin)
  into hepatocytes
• Conjugation
• Transport in bile ( gall)

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DEGRADACE Hb

• Globin je odstranen
• Cervený hem je degradován v endoplasmatickém
  retikulu (játra, slezina,kostní dren) pomocí
  NADPH oxygenasy
• biliverdin a bilirubin vznikají
• Transport of bilirubinu (ve vazbe na albumin) do
  hepatocytu
• Konjugace
• Transport ve luci

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Degradation of Hb

• Icterus
• pre-, intra- and posthepatal
• origin

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IRON METABOLISM
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Text to previous slide Control of mammalian
iron metabolism

• Transport molecule of iron is transferrin
• (glycoprotein, m.w. 80 kDa contains two
  binding sites - both sites are structural very
  similar, functional different under
  physiological state only about 30 are
  occupied).
• High level of iron in body (all positions are
  occupied) then, non- transferrin- bound iron
  appears.

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IRON

• Iron is localized in hemoproteins Hb, ferritin
  - transport protein - quantity - see two next
  slides, myoglobin, cytochromes - see also
  previous slide, furthermore, aconitase (enzyme
  from Krebs cycle, here Fe - ions are bound to
  S), NADPH oxidase
• Toxic effect of iron (Haber Weiss- Fenton
  reactions)
• Fe2 O2 ? Fe3 .O2-
• 2 .O2- 2H ? H2O2
  2 O2
• Fe2 H2O2 ? Fe3 .OH
  OH-
• Formation of hydroxyl radical .OH, it means
  the production of free radicals see special
  lecture for details
• Inhibition of oxidation of Fe2 to Fe3 is
  done by either with ceruloplasmin, or by
  binding of Fe2 to tranferrin, ferritin,
  lactoferrin or iron chelatation

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Text to next slide

• Fig. 2 (lower) - Intestinal iron uptake
• iron from nutrition is absorbed to
  enterocytes of duodenum in both heme form (from
  animal sources) via heme carrier protein HCP in
  enterocates is degradated by hemeoxygenase 1 HO
  -1 and non- heme form (from plants) via
  DMT1 divalent metal transporter after their
  reduction by duodenum cytochrome b-like
  ferrireductase (Dcytb) in the presence of
  ascorbic acid or some AAs (cystein, histidin)
• Fig 3 (upper) - Recirculation of erythocytes
  iron in macrophage,
• Ery - life span 120 days, then Ery in
  reticulo-endothelial system of macrophages
  degradated, Hb is released globin (Gb) and
  heme structure persisted releasing of Fe 2 is
  done by DMT1 (divalent metal transporter -
  intracellular pool of iron. In plasma is bound
  to haptoglobin (Hp), into cell is transfered by
  receptor CD 136 where iron is release by
  hemoxygenase HO 1

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Recirculation of erythrocyte Fe in macro-phage
(fig.3) Intestinal Fe uptake (fig. 2)
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Haptoglobin (Hp)

• Glycoprotein (two a chains, two ß chains) is
  formed in liver
• Haptoglobin bound Hb and complex (C) arised
  Hp-Hb
• C is removed from blood stream by RES
• Physiological role probably block again
• formation of hydroxyl radical (.OH)
• - see oxidation of iron

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Bilirubin

• Bilirubin (B) je vázán na albumin (1 vysoko- a 1
  nizkoaffinitní místo 25 mg B/ 100 ml plasma
• 1g Hb 35 mg B, produkce 250 - 350 mg B/den
• Dva typy B
• Prímý B konjugovaný
• Neprímý B nekonju-
• govaný

• Bilirubin (B) is bound to albumin (1 high, and 1
  low-affinity sites 25 mg B /100 ml of plasma
• 1g Hb 35 mg B, production 250 - 350 mg B/day
• Two types of B
• Direct B conjugated
• Indirect B unconju-
• gated

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Clinical aspects

• Serum Urine
  Urine fecal
• B B
  u r o b i l i n o g e n
• total up 1mg/dL absent 0-4/24h
  40-280/24h
• direct 0,1-0,4
• Indirect 0,2-0,7
• 1mg 17,1µmol/l
• i c t e r u s
  loutenka
• hemolytic ? indirect absent ?
  ?
• hepatitic ? dir, ind present
  ? ?
• obstruct ? dir present
  absent trace to 0
• d bilirubin ( high direct B then arised
  covalent binding between direct B and albumin -
  longer life time than conventional direct B)
• Most of colorless urobilinogens formed in colon
  by fecal flora are oxidized to urobilinins
  (darkening of feces upon air is due to oxidation
  of residual urobilinogens)

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Gene determined abnormalitites

• Fotosensitivita a neurologické problémy jsou
  projevem tohoto onemocnení
• Erytrocyty a játra jsou hlavní místem
  metabolických vyjádrení porfyrií.

• Photosensitivity and neurological problems are
  common complaints.
• Erytrocytes and liver are main places of
  metabolic disorders of porphyrias.

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Further information

• Series of hereditary and acquired diseases
  porphyrias disturbances in porphyrin metabolism
• Several of these disorders excretion of heme
  precursors in the stool or urine - giving them
  dark collor
• Accumulation of porphyrins in the skin
  exposure to light causes disfiguring (znetvorení,
  zohyzdení), poorly - healthing blisters (puchýre)
• Neurological disturbances
• Human vampiers porphyria sufferers (lights
  shynness, bizare appearance, drinking of blood
  to compensate heme deficinecy)

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Bile pigments x bile lucová barviva
acids !!! lucové kyseliny!!!

• lucová barviva bilirubin, biliverdin
• (metaloproteiny)
• lucové kyseliny primarní (cholová k.
• v slabe alkalickém pH luci jako anion cholat),
  sekundární (deoxycholová, lithocholová)
• (steroidní struktura odvozená od cholesterolu)

• Bile pigments bilirubin, biliverdin
• (metaloproteins)
• Bile acids primary (cholic a. cholate and in
  weakly alkaline pH of bile as anion cholate),
  secondary acids (deoxycholic, lithocholic )
• (steroid structure derived from cholesterol)