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 (AM)

enzyme:uroporphrinogen decarboxylase

• Coproporphyrinogen III enters the mitochondria protoporphyrinogen III protoporphyrin III

oxidase

oxidase

• 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

-ALAS1HEPATİC -ALAS2ERYTHROİD

• 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)

• Treatment:– Symptomatic– Avoid drugs that induce cyt P450– Glucose _loading– Hematin administration– β carotenePhotosensitivity decreases