680
chapter 29
Metabolism of Iron and Heme
At low cytosolic mobile iron pool :
IRP levels increase and bind to mRNA-IREs
of ferritin and transferrin receptors.
IRP^
'IRE
Inactive ferritin mRNA
IRP
IRE
'An3
At high cytosolic mobile iron pool :
IRP levels decrease causing opposite
effects on the mRNAs.
G
IRE
-UTR-
Coding Region
Active ferritin mRNA
IRE
'A n
3
FIGURE 29-3
Coordinate translational regulation of ferritin mRNA and transferrin receptor mRNA in nonerythroid cells. Iron
regulatory proteins (IRP) are RNA-binding proteins that bind to iron regulatory elements (IREs). IREs are hairpin
structures with loops consisting of CAGUGN sequences and are located at the 5'-untranslated region (UTR) and
3'-UTR for ferritin mRNA and transferrin mRNA, respectively.
during intracellular chelatable iron excess or iron-replete
states. A coordinated control occurs when IRP binds to
IRE at the 5'-UTR of ferritin mRNAs inhibiting ferritin
synthesis; simultaneously, the binding of IRP to IRE at the
3'-UTR of transferrin receptor mRNA stimulates transfer-
rin receptor synthesis (Figure 29-3). Intracellular iron reg-
ulates the level of IRPs. During the expansion of the iron
pool, IRPs are inactivated, leading to efficient translation
of ferritin mRNA and rapid degradation of transferrin re-
ceptor mRNA. In iron-replete cells, IRP1 acquires iron by
the formation of iron-sulfur clusters (4Fe-4S) that bind to
IREs with low affinity. During iron deficiency states, IRP1
lacks a 4Fe-4S cluster and binds to IREs with high affinity.
IRP1, when it possesses an iron-sulfur cluster, has aconi-
tase activity, normally TCA cycle enzyme (Chapter 14).
Mutations that change IREs can lead to constitutive fer-
ritin biosynthesis. An autosomal dominant disorder of IRE
leads to
hyperferritinemia
without any iron overload. Pa-
tients with this inherited disorder also exhibit early onset
of cataract that may also be cotransmitted as an autosomal
dominant trait. Other factors also regulate ferritin synthe-
sis. For example, nitric oxide enhances binding of IRP
to IRE and inhibits ferritin synthesis. One of the causes
of anemia of chronic inflammatory diseases may be due
to increased ferritin synthesis in the reticuloendothelial
macrophages by inflammatory cytokines interleukins
1
and
6
(IL-1 and IL-
6
), which act by preventing efficient
release of iron.
Measurement of serum ferritin levels has diagnostic
utility. In iron deficiency anemia (discussed later), serum
ferritin levels are low; in iron storage disease, the levels are
high. However, serum ferritin levels can also be elevated
under many other circumstances, including liver diseases
and chronic inflammatory diseases.
Alterations of Plasma Transferrin Concentration
Plasma transferrin levels are commonly measured in
the evaluation of disorders of iron metabolism (see be-
low). It is customary to measure transferrin concentration
