Download 2-Heme Synthesis

Heme Synthesis
Dr. Shumaila Asim
Lecture # 2
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Overview of Heme Synthesis
Heme
Succinyl CoA + Glycine
Protoporphyrin IX
ALA synthase
-aminolevulinic acid
Protoporphyrinogen IX
Coproporphyrinogen III
mitochondrial matrix
cytoplasm
-aminolevulinic acid
Porphobilinogen
Uroporphyrinogen III
Uroporphyrinogen I
Coproporphyrinogen III
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.
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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
GLYCINE + SuccinylCoA
ALA synthase
-aminolevulinic acid(ALA)
ALA dehydratase
Porphobilinogen(PBG)
hydroxymethylbilane
uroporphyrinogen III
coprophyrinogen III
Protoporphyrinogene IX
protoporphyrin IX
Heme
PBG deaminase
Uroporphyrinogen III
cosynthase
Uroporphyrinogen
decarboxylase
Coproporphyrinogen
oxidase
Protoporphyrinogen
oxidase
Ferrochelatase
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
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.
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Porphobilinogen (PBG)
• ALA leaves the mitochondria → cytoplasm
• 2x ALA condense together to form porphobilinogen
• reaction is catalyzed by porphobilinogen synthase
(ALA dehydratase)
COO
N
H
pyrrole
Porphobilinogen
(PBG) is the first
pathway intermediate
that includes a
pyrrole ring.
COO
CH2
CH2
CH2
H2C
NH3
+
N
H
Porphobilinogen (PBG)
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.
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COO-
-
OOC
CH2
COO-
CH2
CH2
CH2
NH
HN
NH
HN
CH2
CH2 COO-
CH2
COO-
HO
CH2
CH2 CH2
CH2
COO-COO-
CH2
hydroxymethylbilane
COO10
COO-
hydroxymethylbilane
-
OOC
COO-
uroporphyrinogen
III
-
CH2
COO-
CH2
COO
CH2
CH2
CH2
CH2
CH2
CH2
NH
HN
NH
HN
CH2 COO-
-
OOC CH2
NH
HN
NH
HN
CH2
CH2 COO-
CH2
COO-
HO
C
C
CH2
C
COO-
-
OOC CH2
C
CH2
CH2 CH2
CH2
COO-COO-
CH2
COO-
Uroporphyrinogen III
Synthase
CH2
CH2
CH2
CH2
COO-
COO-
Uroporphyrinogen III Synthase converts the linear
tetrapyrrole hydroxymethylbilane to the macrocyclic
uroporphyrinogen III.
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-
COO
-
protoporphyrin IX
uroporphyrinogen III
CH2
COO-
CH2
CH2
CH2
CH
OOC CH2
CH2
-
CH2 COO
CH3
CH CH2
H3C
NH
HN
NH
NH
HN
N
-
CH2
OOC CH2
COO-
N
HN
H3C
CH3
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
COO-
COO-
COO-
COO-
 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). 12
CH2
protoporphyrin IX
CH2
CH
CH3
CH
CH CH2
H3C
NH
N
N
Fe++
heme
CH3
CH CH2
H3C
Fe
HN
N
H3C
CH3
CH2
CH2
CH2
COO-
N
N
2H+
N
H3C
Ferrochelatase
CH3
CH2
CH2
CH2
CH2
CH2
COO-
COO-
COO-
Fe++ is added to protoporphyrin IX via Ferrocheletase, a
homodimeric enzyme containing 2 iron-sulfur clusters.
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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.

Disorders of Heme Synthesis
• Acquired: Lead poisoning
• Congenital: Porphyrias
• Deficiency of heme has far-reaching effects (hemoglobin,
cytochromes, etc.)
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