Transcript HEM SYNTHES S1.31 MB

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 :
_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 (C20H14N4)
• The substituents :
A:acetate
P:propionate
V:vinly(_CH_CH2)
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)
• 4 mol of PBG condense to form a linear
tetrapyrole, hydroxymethybilane(HMB)
enzyme:uroporphrinogen I synthase(PBG
deaminase , HMB synthase)
• HMB cyclizes spontaneously to form
uroporphyrinogen I or is converted to
uroporphyrinogen III by uroporphyrinogen III
synthase
-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.
• Uroporphrinogen III and I are converted to
porphyrinogen III and I by decarboxylation
(AM)
enzyme:uroporphrinogen
decarboxylase
• Coproporphyrinogen III enters the
mitochondria oxidase protoporphyrinogen
III oxidase protoporphyrin III
• Formation of heme involves incorporation
of ferrous iron into protoporphyrin
enzyme:ferrochelatase(heme synthase)
location:mitochondria
• 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)
Clinical γ family history
• Diagnosis
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)
• Treatment:
– Symptomatic
– Avoid drugs that induce cyt P450
– Glucose _loading
– Hematin administration
– β carotenePhotosensitivity decreases