C o A S H . C O
\I . \ \ U ,.i
-A m inolevulinic acid (A L A )
Protoporphyrinogen IX — Proto gen ^
A lA dehydratase
Porphohlinogcn (PB(i )
Uro gen III
« ' I
Uroporphyrinogen III (Lro’gen III)
( oproporphyrinogen III (Copro gen III)
Biosynthetic pathw ay of heme. The pathw ay consists o f eight irreversible reactions, four each in the m itochondrion and
the cytosol. T he prim ary site o f regulation is the A LA synthase step.
octamer of the enzyme, and they are bound via the reduced
thiol groups. Zinc is required for enzyme activity.
The reaction mechanism consists of Schiff base for-
mation by the keto group of one molecule of ALA with
the e-amino group of a lysyl residue of the enzyme, fol-
lowed by nucleophilic attack by the enzyme-ALA an-
ion on the carbonyl group of a second ALA molecule
with elimination of water. Then, a proton is transferred
from the amino group of the second ALA molecule to the
e-amino group of the lysyl residue with formation of PBG.
Lead is a potent inhibitor of ALA dehydratase, presum-
ably by displacement of zinc by lead because the lead-
inhibited enzyme can be reactivated by the addition of
zinc. ALA dehydratase is inhibited competitively by suc-
which occurs in urine and blood in hereditary tyrosinemia
(Chapter 17). Genetic deficiency of ALA dehydratase is
known to occur.
Formation of Uroporphyrinogen III
Uroporphyrinogen III formation occurs in the cytosol and
requires the successive action of porphobilinogen deam-
inase (or methylbilane synthase) and uroporphyrinogen
III synthase. Porphobilinogen deaminase catalyzes con-
densation of four porphobilinogen molecules in a sym-
metrical head-to-tail arrangement to form a straight-chain
tetrapyrrole, hydroxymethylbilane. Uroporphyrinogen III
synthase catalyzes the rearrangement of one of the pyr-
role rings (ring D in Figure 29-5) to form an asymmetrical
tetrapyrrole, followed by its cyclization to form uropor-
phyrinogen III. In the absence of uroporphyrinogen III
synthase (e.g., in congenital erythropoietic porphyria), the
hydroxymethylbilane cyclizes spontaneously to the uro-
porphyrinogen I isomer, which is not a precursor of heme
Formation of Coproporphyrinogen III
Cytosolic uroporphyrinogen decarboxylase catalyzes suc-
cessive decarboxylation of the four acetic groups to yield
four methyl groups (Figure 29-6).
Formation o f Protoporphyrinogen IX
Mitochondrial coproporphyrinogen oxidase is localized
in the intermembrane space and is probably loosely bound
to the outer surface of the inner membrane. It catalyzes the
successive conversion of propionic acid groups of ring A
and ring B to vinyl groups (Figure 29-7).
Formation o f Protoporphyrin IX and Heme
Both of these steps occur in mitochondria (Figure 29-8).
Porphyrinogen oxidase removes six hydrogen atoms (four
from methane bridge carbons and two from pyrrole nitro-
gens) from protoporphyrinogen to yield protoporphyrin.
The oxidase has an absolute requirement for oxygen. Pro-
toporphyrinogen can also be oxidized nonenzymatically
to protoporphyrin at physiological pH, temperature, and
aerobic conditions. Protoporphyrin oxidase is bound to the