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HEME SYNTHESIS

HEME SYNTHESIS. Prof.Dr.Arzu SEVEN. HEME SYNTHESIS. Heme is synthesized from porphyrins and iron. Porphyrins are cyclic compounds formed by the linkage of four pyrole rings through –HC =methenyl bridges. A characteristic property of porphyrins is to form complex with metal ions :

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HEME SYNTHESIS

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  1. HEME SYNTHESIS Prof.Dr.Arzu SEVEN

  2. HEME SYNTHESIS • Heme is synthesized from porphyrins and iron. • Porphyrins are cyclic compounds formed by the linkage of four pyrole rings through –HC =methenyl bridges

  3. A characteristic property of porphyrins is to form complex with metal ions : _iron porhyrins heme _mg containing porphyrins chlorophyll

  4. Metalloporphyrins and hemoproteins are important in nature . • Natural porphyrins have substutient side chains for the 8 hydrogen atoms on the porphrin nucleus (C20H14N4) • The substituents : A:acetate P:propionate V:vinly(_CH_CH2) M:methyl

  5. A porhyrin with a completely symmetric arrangement of substituents is classified as type I porphyrin

  6. A porphyrin with asymetric substitution in ring IV is classified as type III porhyrin • Only types I and III are found in nature, type III series are for more abundant • Heme and its immediate precursor -protoporphyrin IX -are type III porphyrins (asymetric distribution of methyl groups in ring IV)

  7. Hem is synthesized from succinyl-CoA and glycine. • Pyroxal phosphate is necessary to activate glycine. • Enzyme: ALA synthase (rate controlling enzyme in porphyrin synthesis in mammalian liver) • location:mitochondria

  8. In the cytosol .2 mol of ALA condense by ALA dehydratase to form 2 mol of H2O and porphobilinojen (PBG) • ALA dehydratase is a zinc containing enzyme, sensitive to inhibition by lead (lead poisoning)

  9. 4 mol of PBG condense to form a linear tetrapyrole, hydroxymethybilane(HMB) enzyme:uroporphrinogen I synthase(PBG deaminase , HMB synthase)

  10. HMB cyclizes spontaneously to form uroporphyrinogen I or is converted to uroporphyrinogen III by uroporphyrinogen III synthase

  11. -the pyrole rings in uroporphyrinogen I and III are connected by methylene bridges(-CH2-) and do not form conjugated ring systems . -All the porphyrinogens are colorless. -They are readily auto_oxidized to their respective colored porphyrins, catalyzed by light and by the porphyrins formed.

  12. Uroporphrinogen III and I are converted to porphyrinogen III and I by decarboxylation (AM) enzyme:uroporphrinogen decarboxylase • Coproporphyrinogen III enters the mitochondria protoporphyrinogen III protoporphyrin III oxidase oxidase

  13. Formation of heme involves incorporation of ferrous iron into protoporphyrin enzyme:ferrochelatase(heme synthase) location:mitochondria

  14. Heme synthesis occurs in most mammalian cells except mature erythrocytes (no mitochondria) • 85% of heme synthesis occurs in erythroid precursor cells in bone marrow, the rest in hepatocytes.

  15. Regulation of heme synthesis: • ALA synthase (ALAS1) is the key regulatory enzyme in hepatic biosynthesis of heme -ALAS1HEPATİC -ALAS2ERYTHROİD

  16. Heme, through an aporepressor molecule, acts as a negative regulator of ALAS1 • Heme affects translation of ALAS1 and its transfer from cytosol to mitochondrion.

  17. Drugs(barbiturates,griseofulvin) that are metabolized in the liver by using cytocrome p450,decrease intracellular heme concentration derepress(induce) ALAS1 heme synthesis increases. • Glucose loading and hematin administration can repress ALAS1 in liver.

  18. PORHYRINS • The characteristic absorption spectrum of porphryrins _the sharp absorbtion band near 400 nm_ is of great value  SORET BAND • When porphyrins,dissolved in strong mineral acids or in organic solvents , are illuminated by UV light,they emit a strong red fluorescence.

  19. The double bonds joining the pyrole rings in the porphyrins are responsible for the characteristic absorption and fluorescence of porphyrins. -At 400 nm the porphyrins react with molecular oxygen to form oxygen radicals. Lysosomes and other organelles are injured Degradative enzymes are released  skin damage (scarring)

  20. Due to the photodynamic properties of porphyrins,they are used in cancer phototherapy.

  21. PORPHYRİA • Disorders due to abnormalities in the heme biosynthesis pathway • Genetic or acquired • Autosomol dominant manner • Congenital erythropoietic porphyria (recessive) • Diagnosis Clinical γfamily history Physical examination Assay of the activity of the responsible enzyme (red blood cells)

  22. Prenatal diagnosis (gene probes) • Porphyrias can be classified according to organs or cells that are most affected :Erythropoietic or hepatic • Drugs that induce cytocrome P 450 can precipitate porphyria attacks. • High levels of LEAD combine with –SH groups of ferrochelatase and ALA dehydratase protoporphyrin (erythrocytes) • ALA ,coproporphyrin (urine)

  23. Treatment: • Symptomatic • Avoid drugs that induce cyt P450 • Glucose _loading • Hematin administration • β carotenePhotosensitivity decreases

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