Page 201 - Color Atlas of Biochemistry

192 Metabolism

Heme biosynthesis chains have to be converted into less polar
groups.
Heme, an iron-containing tetrapyrrole pig- [5] Initially, the four acetate residues (R 1 )
ment, is a component of O 2 -binding proteins are decarboxylated into methyl groups. The
(see p. 106) and a coenzyme of various oxi- resulting coproporphyrinogen III returns to
doreductases (see p. 32). Around 85% of heme the mitochondria again. The subsequent steps
biosynthesis occurs in the bone marrow, and a are catalyzed by enzymes located either on or
much smaller percentage is formed in the inside the inner mitochondrial membrane.
liver. Both mitochondria and cytoplasm are [6] An oxidase first converts two of the
involved in heme synthesis. propionate groups (R 2 )into vinyl residues.
The formation of protoporphyrinogen IX com-
pletes the modification of the side chains.
A. Biosynthesis of heme
[7] In the next step, another oxidation pro-
Synthesis of the tetrapyrrole ring starts in the duces the conjugated π-electron system of
mitochondria. protoporphyrin IX.
[1] Succinyl CoA (upper left), an intermedi- [8] Finally, a divalent iron is incorporated
ate in the tricarboxylic acid cycle, undergoes into the ring. This step also requires a specific
condensation with glycine and subsequent enzyme, ferrochelatase. The heme b or Fe-pro-
decarboxylation to yield 5-aminolevulinate toporphyrin IX formed in this way is found in
(ALA). The ALA synthase responsible for this hemoglobin and myoglobin, for example (see
step is the key enzyme of the whole pathway. p. 280), where it is noncovalently bound, and
Synthesis of ALA synthase is repressed and also in various oxidoreductases (see p. 106).
existing enzyme is inhibited by heme, the
end product of the pathway. This is a typical Further information
example of end-product or feedback inhibi-
tion. There are a large number of hereditary or
[2] 5-Aminolevulinate now leaves the mi- acquired disturbances of porphyrin synthesis,
tochondria. In the cytoplasm, two molecules known as porphyrias, some of which can
condense to form porphobilinogen, acom- causesevereclinical pictures. Several of these
pound that already contains the pyrrole ring. diseases lead to the excretion of heme pre-
Porphobilinogen synthase is inhibited by lead cursors in feces or urine, giving them a dark
ions. This is why acute lead poisoning is asso- red color. Accumulation of porphyrins in the
ciated with increased concentrations of ALA skin can also occur, and exposure to light then
in the blood and urine. causes disfiguring, poorly healing blisters.
[3] The tetrapyrrole structure characteristic Neurological disturbances are also common
of the porphyrins is produced in the next in the porphyrias.
steps of the synthetic pathway. Hydroxyme- It is possible that the medieval legends
thylbilane synthase catalyzes the linkage of about human vampires (“Dracula”) originated
four porphobilinogen molecules and cleavage in the behavior of porphyria sufferers (avoid-
of an NH 2 group to yield uroporphyrinogen III. ance of light, behavioral disturbances, and
[4] Formation of this intermediate step re- drinking of blood in order to obtain heme—
quires a second enzyme, uroporphyrinogen III which markedly improves some forms of por-
synthase. If this enzyme is lacking, the phyria).
“wrong” isomer, uroporphyrinogen I, is
formed.
The tetrapyrrole structure of uroporphyri-
nogen III is still very different from that of
heme. For example, the central iron atom is
missing, and the ring contains only eight of
the 11 double bonds. In addition, the ring
system only carries charged R side chains
(four acetate and four propionate residues).
As heme groups have to act in the apolar
interior of proteins, most of the polar side

Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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