
Iron – Absorption, Transport, and Loss
0004 Iron is readily absorbed in the state Fe
2þ
, but most
dietary iron is in the ferric form Fe
3þ
. The gastric
secretions dissolve the iron and permit it to form
soluble complexes with ascorbic acids and other sub-
stances that aid its reduction to the Fe
2þ
form. In
humans iron-deficiency anemia is a relatively fre-
quent complication of partial gastrectomy. Heme is
also absorbed because of its solubility. Fe
2þ
contained
in heme is released into mucosal cells.
0005 Iron is absorbed from the upper part of the small
intestine, because duodenum and adjacent jejunum
contain most mucosal cells suitable for iron absorp-
tion. Various dietary factors influence iron absorption,
for example, phytic acid from cereals, which forms
iron-insoluble compounds in the intestine, as do
phosphates and oxalates.
0006 Nonheme iron binds to mucin. Cell adhesion mol-
ecule integrin transfers the iron to mobilferrin.
Mobilferrin carries iron into the cell and binds more
iron in iron-deficiency states. The mucosal cells
contain iron-binding protein, or apoferritin. Some
iron is utilized by mitochondria, and the remainder
is partitioned between apoferritin in the mucosal cells
and transferrin. Transferrin is a protein that carries
iron in the blood. Specific cell-surface receptors de-
liver the transferrin with its bound iron to endosomes.
Here the low pH induces the separation of transferrin
and the iron. Excess iron in the blood is deposited in
all cells of the body, especially in liver cells. Apoferri-
tin is also found in many other tissues, where, to-
gether with iron, it forms ferritin. Apoferritin is a
globular protein. Iron forms a micelle of ferric hydro-
xyphosphate. In ferritin 24 subunits of protein sur-
round each micelle. The ferritin micelle can contain
4500 atoms of iron. It is the iron storage form in
tissues. Molecules of ferritin may aggregate in lysoso-
mal membranes as deposits, containing up to 50%
iron. These deposits are called hemosiderin.
0007 Iron is also transported across the placenta from
mother to fetus. Maternal iron plasma concentration
is usually lower than fetal concentration. However,
the binding capacity of maternal plasma for iron is
much higher, even though iron is actively transported
into the fetal compartment. A daily transport
of about 1.8 mmol is necessary to meet total fetal
requirements.
0008 In adult humans, the amount of iron lost from the
body is relatively small. It is unregulated, and total
body stores of iron are regulated by changes in the
rate at which iron is absorbed. Men lose about 0.6 mg
day
1
, whereas women have a variable, larger loss
because of the additional iron lost in blood shed
during menstruation.
Biosynthesis and Significance of Heme
0009Evolution of higher organisms has been accompanied
by the development of oxygen transport protein. In
humans this protein – hemoglobin – is concentrated
in specialized cells – erythrocytes. Each erythrocyte
contains about 300 million hemoglobin molecules.
The organic structure of a protein is unable to direct
binding of oxygen. However, certain metals, in their
lower oxidation states (for example, Fe
2þ
) have a
strong tendency to bind oxygen. Thus, in the evolu-
tion of the hemoglobin–myoglobin family of proteins,
Fe
2þ
has been utilized in the O
2
-binding site.
0010There are a number of possibilities in which vari-
ous iron-containing proteins hold iron in the form
Fe
2þ
. Hemoglobin and myoglobin are a family of
proteins, in which iron is chelated by the tetrapyrrole
ring system – protoporphyrin IX. It is one protein in a
large class of porphyrins, which are also encountered
in chlorophyl, cytochrome proteins, and other nat-
ural pigments. The porphyrins are colored. The iron
porphyrin in hemoglobin accounts for the red color of
blood. The complex of protoporphyrin IX with Fe
2þ
is called heme. Ferrous iron is octahedrally coordin-
ated, which means it should have six ligands or bind-
ing groups attached to it. The nitrogen atoms of the
porphyrin ring account for only four ligands. Two
remaining available coordination sites lie along an
axis perpendicular to the plane of the ring. In myo-
globin one of these sites is occupied by nitrogen of
histidine (part of the protein helix).
0011When oxygen is bound, the O
2
molecule occupies
the vacant side. Hemoglobin has evolved from myo-
globin and forms a tetrameric structure. Each of the
four chains in hemoglobin has a folded structure
similar to that of myoglobin, and each carries a
heme. Hemoglobin contains four subunits: two
a-chains and two b-chains. Both chains are very simi-
lar but are distinguishable in primary structures and
folding. Each subunit has primary, secondary, and
tertiary structures. Amino acid side chains in hemo-
globin provide hydrophobic, salt bridges, and hydro-
gen bond interactions. These are necessary to stabilize
a particular quaternary structure.
0012Each hemoglobin molecule can bind four oxygen
molecules, in four myoglobin-like sites. To simplify,
we can consider hemoglobin as having two states of
quaternary structure: one characteristic for the deoxy
form and the other for the oxygenated form. The oxy
form has a higher affinity for O
2
. The transition from
the deoxy to the oxy conformation involves changes
in the interactions between the subunits. A ligand
oxygen, binding to its side, tends to pull the Fe
2þ
a
very short distance down into the heme and flattens
the heme. Consequently, a molecular rearrangement
3380 IRON/Biosynthesis and Significance of Heme (Haem)