684
chapter 29
Metabolism of Iron and Heme
disease in the general population has been suggested. The
biochemical tests include the measurement of serum levels
of iron, transferrin saturation, and ferritin.
29.2 Heme Biosynthesis
The principal tissues involved in heme biosynthesis are the
hematopoietic tissues and the liver. Biosynthesis requires
participation of eight enzymes, of which four (the first and
the last three) are mitochondrial and the rest are cytosolic
(Figure 29-4). The reactions are irreversible. Glycine and
succinate are the precursors of porphyrins.
Formation of (5-Aminolevulinic Acid
(5-Aminolevulinic acid (ALA ) formation is catalyzed by
mitochondrial ALA synthase, which condenses glycine
and succinyl-CoA to ALA. The enzyme is located on the
matrix side of the inner mitochondrial membrane. It is
encoded by a nuclear gene and is synthesized in the cytosol
on the free polyribosomes as a
CO O H
COOH
isonicotinic acid hydrazide; Chapter 17) can prevent heme
synthesis and cause anemia. Heme synthesis also requires
a functional tricarboxylic acid cycle and an oxygen supply.
The primary regulatory step of heme synthesis in the
liver is apparently that catalyzed by ALA synthase. The
regulatory effects are multiple. The normal end product,
heme, when in excess of need for production of heme pro-
teins, is oxidized to
hematin,
which contains a hydroxyl
group attached to the Fe3+ atom. Replacement of the
hydroxyl group by a chloride ion produces
hemin.
Hemin
and heme inhibit ALA synthase allosterically. Hemin also
inhibits the transport of cytosolic ALA synthase precursor
protein into mitochondria.
ALA synthase has a turnover rate of 70 minutes in adult
rat liver and is inducible. Its induction is suppressed by
hemin and increased by a variety of xenobiotics (e.g., en-
vironmental pollutants) and natural steroids. In erythro-
poietic tissues, where the largest amount of heme is
synthesized, regulation of heme biosynthesis may also in-
volve the process of cell differentiation and proliferation
of the erythron, which occurs to meet change in require-
ments for the synthesis of heme. The differentiation and
proliferation are initiated by erythropoietin.
C H 2
I
.
C H 2 + C 0 2 + CO ASH
I
c = o
I
C H 2
I
n h 2
Glycine
Succinyl-CoA
^-Aminolevulinic acid
precursor. The precursor protein is processed to active
form during its translocation into mitochondria (Chap-
ter 25). Pyridoxal phosphate is the required coenzyme.
The reaction mechanism consists of formation of a
Schiff base by pyridoxal phosphate with a reactive amino
group of the enzyme; entry of glycine and formation of
an enzyme-pyridoxal phosphate-glycine-Schiff base com-
plex; loss of a proton from the
a
carbon of glycine with the
generation of a carbanion; condensation of the carbanion
with succinyl-CoA to yield an enzyme-bound intermedi-
ate (a-amino-/3-ketoadipic acid); decarboxylation of this
intermediate to ALA; and liberation of the bound ALA
by hydrolysis. ALA synthesis does not occur in mature
erythrocytes.
In experimental animals, deficiency of pantothenic acid
(needed for CoASH and, hence, succinyl-CoA synthe-
sis), lack of vitamin B6, or the presence of compounds
that block the functioning of pyridoxal phosphate (e.g.,
COOH
C H ,
+ C H 2
C H 2— NH2
I
C — SCoA
Pyridoxal
phosphate
Formation of Porphobilinogen
Two molecules of ALA are condensed by cytosolic zinc
containing ALA dehydratase to
COOH
I
C H 2
I
C H 2
2
I
c = o
I
C H 2
I
NH2
ALA
—2H?0
Acetic
acid
substituent
(A)
H2C
CO O H
CO O H C H 2
I
I
C H 2
C H 2
!
I
c -------c
H
n h
2
Propionic
acid
substituent
(P)
Porphobilinogen
yield porphobilinogen (PBG). There are four zinc ions per
