Text of HEME SYNTHESIS Prof.Dr.Arzu SEVEN. HEME SYNTHESIS Heme is synthesized from porphyrins and iron....
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HEME SYNTHESIS Prof.Dr.Arzu SEVEN
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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
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A characteristic property of porphyrins is to form complex with
metal ions : _iron porhyrins heme _mg containing porphyrins
chlorophyll
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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
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A porhyrin with a completely symmetric arrangement of
substituents is classified as type I porphyrin
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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)
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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
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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)
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4 mol of PBG condense to form a linear tetrapyrole,
hydroxymethybilane(HMB) enzyme:uroporphrinogen I synthase(PBG
deaminase, HMB synthase)
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HMB cyclizes spontaneously to form uroporphyrinogen I or is
converted to uroporphyrinogen III by uroporphyrinogen III
synthase
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-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.
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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
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Formation of heme involves incorporation of ferrous iron into
protoporphyrin enzyme:ferrochelatase(heme synthase)
location:mitochondria
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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.
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Regulation of heme synthesis: ALA synthase (ALAS1) is the key
regulatory enzyme in hepatic biosynthesis of heme -ALAS1 HEPATC
-ALAS2 ERYTHROD
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Heme, through an aporepressor molecule, acts as a negative
regulator of ALAS1 Heme affects translation of ALAS1 and its
transfer from cytosol to mitochondrion.
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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.
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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.
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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)
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Due to the photodynamic properties of porphyrins,they are used
in cancer phototherapy.
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PORPHYRA Disorders due to abnormalities in the heme
biosynthesis pathway Genetic or acquired Autosomol dominant manner
Congenital erythropoietic porphyria (recessive) Diagnosis Clinical
family history Physical examination Assay of the activity of the
responsible enzyme (red blood cells)
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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)
