1. Dr. Shumaila Asim Lecture # 2
Heme Synthesis
Dr. Shumaila Asim
Lecture # 2

2. Overview of Heme Synthesis
Succinyl CoA + Glycine
Protoporphyrin IX
ALA synthase
Protoporphyrinogen IX
-aminolevulinic acid
Coproporphyrinogen III
mitochondrial matrix
cytoplasm
-aminolevulinic acid
Uroporphyrinogen III
Coproporphyrinogen III
Porphobilinogen
Uroporphyrinogen I
Coproporphyrinogen I
Heme synthesis occurs in all cells due to the requirement for heme as a prosthetic group on enzymes and electron transport chain. By weight, the major locations of heme synthesis are the liver and the erythroid progenitor cells of the bone marrow.

3. Heme biosynthesis in bone marrow (85% of Hb) and liver (cytochromes)
cell location: mitochondria / cytoplasm / mitochondria
substrates: succinyl-CoA + glycine
important intermediates:
δ-aminolevulinic acid (= 5-aminolevulinic acid, ALA)
porphobilinogen (PBG = pyrrole derivate)
uroporphyrinogen III (= porphyrinogen – heme precursor)
protoporphyrin IX (= direct heme precursor)
● key regulatory enzyme: ALA synthase

4. d-aminolevulinic acid(ALA)
GLYCINE + SuccinylCoA
ALA synthase
d-aminolevulinic acid(ALA)
ALA dehydratase
Porphobilinogen(PBG)
PBG deaminase
hydroxymethylbilane
Uroporphyrinogen III
cosynthase
uroporphyrinogen III
Uroporphyrinogen
decarboxylase
coprophyrinogen III
Coproporphyrinogen
oxidase
Protoporphyrinogene IX
Protoporphyrinogen
oxidase
protoporphyrin IX
Ferrochelatase
Heme

5. δ-aminolevulinic acid (ALA)
synthesis of heme starts in mitochondria
succinyl-CoA and Gly undergo a condensation → ALA
reaction is catalyzed by enzyme ALA synthase

7. ALA Synthase is the committed step of the heme synthesis pathway, & is usually rate-limiting for the overall pathway.
Regulation occurs through control of gene transcription. 
Heme functions as a feedback inhibitor, repressing transcription of the ALA Synthase gene in most cells.

8. Porphobilinogen (PBG)
ALA leaves the mitochondria → cytoplasm
2x ALA condense together to form porphobilinogen
reaction is catalyzed by porphobilinogen synthase
(ALA dehydratase)

9. Porphobilinogen (PBG) is the first pathway intermediate that includes a pyrrole ring.
The porphyrin ring is formed by condensation of 4 molecules of porphobilinogen. 
Porphobilinogen Deaminase catalyzes successive PBG condensations, initiated in each case by elimination of the amino group.

11. Uroporphyrinogen III Synthase converts the linear tetrapyrrole hydroxymethylbilane to the macrocyclic uroporphyrinogen III.

12. All 4 acetyl side chains are decarboxylated to methyl groups (catalyzed by Uroporphyrinogen Decarboxylase)
Oxidative decarboxylation converts 2 of 4 propionyl side chains to vinyl groups (catalyzed by Coproporphyrinogen Oxidase)
Oxidation adds double bonds (Protoporphyrinogen Oxidase).

13. Fe++ is added to protoporphyrin IX via Ferrocheletase, a homodimeric enzyme containing 2 iron-sulfur clusters.

14. Regulation of heme biosynthesis
ALA synthase is a key regulatory enzyme
● it is an allosteric enzyme that is inhibited by an end product - heme (feedback inhibition)
● requires pyridoxal phosphate as a coenzyme
● certain drugs and steroid hormones can increase heme synthesis
Porphobilinogen synthase is inhibited by lead ions Pb2+ in case of lead poisoning.
Ferrochelatase (heme synthase) can be also inhibited by Pb2+. Its activity is influenced by availability of Fe2+ and ascorbic acid.

15. Disorders of Heme Synthesis
Acquired: Lead poisoning
Congenital: Porphyrias
Deficiency of heme has far-reaching effects (hemoglobin, cytochromes, etc.)