section 29.1
Iron Metabolism
679
about 20-23 mg. Increased menstrual flow (
menorrhagia
)
significantly augments iron loss and leads to iron defi-
ciency anemia (see below). In pregnancy use of supple-
mental iron is recommended. A newborn has about a 3- to
6
-month supply of iron in its liver and may require iron-
rich foods from the sixth month onward, since milk is poor
in iron.
Plasma Iron Transport
Over 95% of plasma iron is in the Fe3+ state bound
to the glycoprotein transferrin, a monomeric
-globulin
(M.W. 80,000). Electrophoretic studies have revealed the
existence of 21 genetic variants. In some, single-amino-
acid substitutions account for variation in electrophoretic
mobility. Transferrin is synthesized primarily in the liver
and appears at the end of the first month of fetal develop-
ment. Its half-life in humans is about
8
days. Desialylation
may be a requirement for its removal from plasma by the
liver, as it is for other plasma proteins (Chapter 10). In
fact, asialotransferrin is more rapidly cleared from plasma
than transferrin. It is not required for intestinal absorption
of iron.
Each molecule of transferrin can bind two Fe3+ ions.
The binding is extremely strong under physiological con-
ditions, and the binding constants of the two sites are not
significantly different. For each Fe3+ bound, one HC07
ion is also bound and three H+ ions are released from the
protein.
Thus, diferric transferrin gains two net negative charges.
2Fe3+ + apotransferrin + 2HCCU —
[Fe
2
-transferrin-(HC
0 3
)
2
]2_ +
6
H+
The metal binding sites are located in N- and C-terminal
domains. The protons released upon binding of each Fe3+
ion are probably derived from ionization of two tyrosyl
residues and of a water molecule bound to Fe3+ ion.
The bulk of transferrin iron is delivered to immature
erythroid cells for utilization in heme synthesis. Iron
in excess of this requirement is stored as ferritin and
hemosiderin. Unloading of iron to immature erythroid
cells is by
receptor-mediated endocytosis.
The process
begins in the clathrin-coated pits with the binding of di-
ferric transferrin to specific plasma membrane transferrin
receptors that are associated with the HFE protein com-
plex. The next step is the internalization of the transferrin-
transferrin receptor-HFE protein complex with formation
of endosomes. The iron transporter DMT1 present in the
cell membrane is also internalized into the endosomes.
In the endosomes, a proton pump acidifies the complex
to pH 5.4, and by altering conformation of proteins, iron
is released from transferrin bound to transferrin receptor
and HFE protein. This process of iron release from the
complex is inhibited by HFE protein. Thus, dysfunctional
HFE protein can cause excessive release of iron from the
transferrin-transferrin receptor-HFE protein complex. In
the acidified endosomes, DMT1 facilitates iron transport
into the cytosol. Both apotransferrin (and a fraction of iron-
bound transferrin) and transferrin receptor are returned to
cell surfaces for reuse. In this type of receptor-mediated en-
docytosis of transferrin-transferrin receptor complex, the
endosomes do not come into contact with lysosomes. The
process is therefore unlike that of low-density lipoprotein
receptor-mediated internalization (Chapter 20).
In the erythroid cells, most of the iron released from
the endosomes is transported into mitochondria for heme
synthesis (discussed later); in nonerythroid cells, the iron
is stored predominantly as ferritin and to some extent as
hemosiderin.
Storage of Iron
There
are
two
storage
forms
of iron,
ferritin
and
hemosiderin. Ferritin is the predominant storage form and
contains diffusable, soluble, and mobile fractions of iron.
Hemosiderin is aggregated deposits resulting from the
breakdown of ferritin in secondary lysosomes and its level
increases progressively with increasing levels of iron over-
load. Apoferritin is a protein shell consisting of 24 subunits
of two types; a light (L) subunit (M.W. 19,000) and a heavy
(H) subunit (M.W. 21,000). The H subunit has ferroxidase
activity and the L subunit facilitates nucleation and min-
eralization of the core made up of hydrated ferric oxide
phosphate complex.
Coordinate Regulation of Iron Uptake and
Storage in Non-Erythroid Cells
Iron uptake is regulated by transferrin receptor and stor-
age of iron as ferritin which occurs post-transcriptionally
for these two proteins. The regulation maintains an op-
timal intracellular-transit-chelatable iron pool for normal
functioning in the body. The regulatory process consists of
an interaction between IREs and IRPs 1 and 2. One copy
of each IRE has been identified in the 5'-untranslated re-
gion of H and L ferritin mRNAs and five copies in the
3'-untranslated region
(UTR)
of transferrin receptor
mRNA. IRE sequences are highly conserved and have a
stem-loop structure with a CAGUGN sequence at the tip of
the loop. IRPs are RNA-binding proteins that bind to IREs
and regulate the translation of the respective mRNAs.
During low levels of intracellular chelatable iron, iron
storage declines due to inhibition of ferritin synthesis;
cellular entry of iron increases due to enhanced transfer-
rin receptor synthesis. An opposing set of events occurs
