When hemoglobin is destroyed, globin is degraded into amino acids, and iron enters the iron pool for

reuse.
The heme is degraded in the ReticuloEndothelial cells of liver, spleen and bone marrow.
The catabolism of heme is carried out in the microsomal fractions of cells by heme oxygenase.
1 gm of hemoglobin yields 35 mg of bilirubin, and the daily formation in adult is about 250-350 mg.
In 100 ml of plasma, about 25 mg of bilirubin can be tightly bound to albumin at its high-affinity site

Regulation of heme synthesis

ALA synthase is the key regulatory enzyme in hepatic biosynthesis of heme.
ALA synthase occurs in hepatic (ALAS1) and erythroid(ALAS2) forms.
Heme acts as a negative regulator of the synthesis of ALAS1.
Heme also affects translation of the enzyme and its transfer from cytosol to mitochondrion.
During metabolism of some drugs →increased utilization of heme by cytochromeP450 →diminishes
intracellular heme concentration →de repression of ALAS1 →increased rate of heme synthesis.

Heme biosynthesis occurs in most mammalian cells, 85% in erythroid precursor cells in bone marrow, and 10%r in the liver.
The two starting materials are succinyl-CoA and glycine.
The initial reaction and the last three steps in porphyrin formation occur in mitochondria, whereas the intermediary steps occur
in cytosol.
If porphyrinproduction exceeds the availability of globin, heme accumulates and is converted to hemin by the oxidation of
Fe2+or Fe3+, that decreases the activity of ALA synthase.
The final step involves incorporation of ferrous iron into protoporphyrinin a reaction catalyzed by ferrochelatase.
Bilirubin transport
 Bilirubin formed in peripheral tissues is transported to the liver by plasma albumin.

Further metabolic processes:

Uptake of bilirubin by liver parenchymal cells

Conjugation of bilirubin with glucoronate in the endoplasmic reticulum by UDP-GT

Secretion of conjugated bilirubin into the bile.

Lead poisoning
The enzyme contains zinc and is very sensitive to lead and other heavy metals.
Inhibition of Porphobilinogen Synthase by Pb++ results in elevated blood ALA, as impaired hemesynthesis leads to de-repression
of transcription of the ALA Synthase gene.
High ALA is thought to cause some of the neurological effects of lead poisoning, although Pb++also may directly affect the
nervous system.
ALA is toxic to the brain, perhaps due to:
•Similar ALA & neurotransmitter GABA (g-aminobutyricacid) structures.
•ALA autoxidation generates reactive oxygenspecies (oxygen radicals).
ALA is a re