Biosynthesis of Heme, Heme Degradation (Catabolism of heme) ,Formation of bilirubin (Uptake and secretion of bilirubin into bile ), Formation and Fates of urobilins, (Clinical Hint) Jaundice
A very large structure that
belongs to porphyrin, Derived from Hemin
amino acids such as:
Glycine and succinyl CoA
Succinyl CoA is not an amino acid instead it
is a metabolite of many amino acids, that
is a final product of their metabolism.
We need to join atoms of heme from
Different sources, one source is
glycine and succinyl CoA, which combine
together in mitochondria by
-aminolevulinic acid synthase
(ALAS1) (In liver)
which release CoA and CO2 and combines other atoms in a molecule called
-aminolevulinic acid (ALA), The rate-limiting step in porphyrin synthesis
*Note: Hemin (Heme with ferric(Fe+3)) is a negative regulator of ALAS1
When heme present in high concentration, Fe+2 gets oxidised to Fe+3.
this reaction is repeated twice to obtain 2 ALA molecules
Cytosolic reactions
these 2 molecules align next to each other and interact in a Dehydration reaction,
releasing 2 H2O molecules, by enzyme -aminolevulinic acid dehydratase
Now, we have a ring structure ( the first pyrrole ring structure was formed which is
a 5-membered ring with nitrogen just like in heme group, two side chains upward
acetate and propionate, one side chain downward methylamine).
, *The ring structure is called Porphobilinogen (-gen means precursor)
*Note: lead is external regulator for this step.
The major sites of heme biosynthesis are:
1. Liver (cytochrome P450), variable rate depending on demands for heme
proteins. >> ALAS1
2. Erythrocyte-producing cells of the bone marrow (hemoglobin), more than
85% of all heme synthesis. >>ALAS2
The initial and last steps in porphyrins formation occur in mitochondria The
intermediate steps occur in the cytosol
Mature RBCs lack mitochondria and are unable to synthesize heme
* ALA is elevated in the anemia seen in lead poisoning.
Now, in next reaction we will repeat the two steps how many times? 4 times
How many ALA molecules we need? 8
(i.e the first step is repeated 8 times
(8 ALAs) and second one 4 times so I have
4 Porphobilinogen molecules)
Now, we will condense these 4 molecules
together so they can form the large
porphyrin ring structure, this happen in
multiple steps first remove nitrogen from
downward side chain by hydroxymethyl
bilane synthase forming the linear
tetrapyrrole, hydroxymethylbilane
*notice that the terminal CH2 molecule
will connect two pyrrole rings together.
hydroxymethylbilane is isomerized and
cyclized (ring closure) by
uroporphyrinogen III synthase to
produce the asymmetric
uroporphyrinogen III.
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