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Heme Synthesis
¾ Site: Partly in the mitochondria and partly in the cytoplasm.
¾ Process begins in the mitochondria because one of the precursors
is found only there.
¾ Since this reaction is regulated in part by the concentration of
heme, the final step (which produces the heme) is also
mitochondrial.
¾ Many of the intermediate steps are cytoplasmic. Notice in the
diagram of the pathway that there is a branch with no apparent
useful end product.
Delta-aminolevulinic acid synthase (ALA synthase)
The delta-aminolevulinic acid synthase (ALA synthase) reaction occurs in
the mitochondria.
Hence, heme has a dual role in decreasing its own rate of synthesis.
The product of the reaction, ALA, diffuses into the cytoplasm, where the
next several steps of heme synthesis occur.
ALA dehydratase reaction
The ALA dehydratase reaction occurs in the cytoplasm; the product is
porphobilinogen
• acetic acid
• propionic acid.
Ferrochelatase
Ferrochelatase adds iron (II) to protoporphyrin IX, forming heme.
• The enzyme requires iron (II), ascorbic acid and cysteine (reducing
agents).
• Ferrochelatase is inhibited by lead.
Physiological regulation of heme synthesis
Substrate availability: iron (II) must be available for ferrochelatase.
Porphyrias
Porphyrias may be divided into two major types.
Erythropoietic porphyria is a defect of porphyrin metabolism of
blood-producing tissues.
Hepatic porphyria is a defect in porphyrin metabolism of the liver.
Either type may be hereditary (caused by a gene defect) or acquired
(due to poisoning).
Examples of Porphyria
Two of the several types of porphyria will serve to illustrate some of the
biochemical issues involved.
• heme
• three molecules of oxygen
• NADPH
The reaction is a cleavage of the ring between the I and II pyrrole rings.
• biliverdin
• carbon monoxide (this is the only endogenous source of carbon
monoxide)
• iron (II)
• NADP+
In the second reaction biliverdin reductase reduces the central
methene bridge of biliverdin, producing bilirubin.
Bilirubin
The high lipid solublity of bilirubin determines its behavior and its
further metabolism.
This increased its water solubility, decreases its lipid solubility and eases
its excretion. Conjugation is accomplished by attaching two molecules of
glucuronic acid to it in a two step process.
Stercobilin