Presentation on theme: "HEME SYNTHESIS Prof.Dr.Arzu SEVEN. HEME SYNTHESIS Heme is synthesized from porphyrins and iron. Porphyrins are cyclic compounds formed by the linkage."— Presentation transcript:
A characteristic property of porphyrins is to form complex with metal ions : _iron porhyrins heme _mg containing porphyrins chlorophyll
Metalloporphyrins and hemoproteins are important in nature. Natural porphyrins have substutient side chains for the 8 hydrogen atoms on the porphrin nucleus (C 20 H 14 N 4 ) The substituents : A:acetate P:propionate V:vinly(_CH_CH 2 ) M:methyl
A porhyrin with a completely symmetric arrangement of substituents is classified as type I porphyrin
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)
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
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)
-the pyrole rings in uroporphyrinogen I and III are connected by methylene bridges(- CH 2 -) 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.
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
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.
Regulation of heme synthesis: ALA synthase (ALAS1) is the key regulatory enzyme in hepatic biosynthesis of heme -ALAS1 HEPATİC -ALAS2 ERYTHROİD
Heme, through an aporepressor molecule, acts as a negative regulator of ALAS1 Heme affects translation of ALAS1 and its transfer from cytosol to mitochondrion.
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.
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.
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)
Due to the photodynamic properties of porphyrins,they are used in cancer phototherapy.
PORPHYRİA Disorders due to abnormalities in the heme biosynthesis pathway Genetic or acquired Autosomol dominant manner Congenital erythropoietic porphyria (recessive) Diagnosis Clinical γ family history Physical examination Assay of the activity of the responsible enzyme (red blood cells)
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)