Chemistry Reference
In-Depth Information
in the 3
0
-untranslated region, binding of the IRPs to the mRNAs protects them against degradation by nucleases.
This results in increased iron uptake and blockage of iron storage and export. When iron is abundant, the IRPs are
no longer active in binding, allowing ferritin and ferroportin mRNAs to be translated and resulting in the
downregulation of transferrin receptor and DMT1 synthesis as a result of the nuclease-catalysed degradation of
their mRNAs. Under these conditions, IRP1 acquires aconitase activity, associated with the incorporation of
a 4Fe4S cluster, whereas IRP2 is condemned, after ubiquitination, to degradation in the proteasome.
Systemic iron homeostasis in mammals depends on the regulation of dietary iron absorption by the enterocytes
of the duodenum and the recycling of iron by macrophages recovered from the breakdown of the haemoglobin
from senescent red blood cells. In hereditary disorders of iron loading, known collectively as haemochromatosis,
iron is deposited in parenchymal cells, transferrin saturation increases, and as the iron load increases, serious
damage results to many tissues, notably liver, endocrine tissues like pancreas, and heart. Hereditary haemo-
chromatosis can be divided into three classes
classical haemochromatosis, juvenile haemochromatosis, and
ferroportin disease. Classical haemochromatosis is associated with mutations in HFE, a gene which encodes
a protein of the major histocompatibility complex, although in rare cases another gene can be involved, the TFR2
gene which codes for a homologue of the major transferrin receptor gene, TFR1. Juvenile haemochromatosis is
a rare form of hereditary haemochromatosis, characterised by early and severe onset of symptoms, particularly
cardiac and endocrine defects. Most patients have mutations in the recently cloned HJV gene (haemojuvelin),
which is expressed in muscle, liver, and heart, but whose function is still unknown. Avery small subset of juvenile
haemochromatosis patients have mutations in the HAMP gene, which codes for the prepro form of hepcidin,
a peptide synthesised by the liver, which is a major regulator of iron metabolism. Hepcidin is positively regulated
by iron and negatively regulated by iron deficiency and hypoxia: it limits intestinal iron absorption and iron release
by macrophages. Ferroportin disease, the third class of hereditary haemochromatosis, is caused by pathogenic
mutations in the gene encoding the iron exporter, ferroportin.
We now have an increasingly detailed understanding of how systemic iron homeostasis is regulated. The first
index of iron loading, increased transferrin saturation, leads to increased levels of Fe
2
-Tf, which is detected by the
liver via a complex pathway involving HFE, TFR2, and HJV, the proteins of three of the genes known to be
mutated in haemochromatosis. Hepatocytes respond to this signal by increased expression of the HAMP gene,
resulting in increased secretion of the regulatory peptide, hepcidin. Circulating hepcidin blocks dietary iron uptake
by the duodenal enterocytes and iron recycling from macrophages, in both cases through internalization of fer-
roportin, which blocks iron export (
Fig. 8.19
). The outcome of this is to decrease serum iron levels, leading
logically to the feedback response of downregulating hepcidin synthesis and secretion. This once again allows
ferroportin to be displayed on the surface of enterocytes and macrophages, allowing them once again to export
iron into the circulation. In classical and juvenile haemochromatosis, mutations in HFE, TFR2, and HJV lead to
downregulation of hepcidin synthesis, decreased levels of circulating hepcidin, and ferroportin hyperactivity. The
latter accounts for the increased iron absorption and uncontrolled release of iron from macrophages, defects
characteristic of hereditary haemochromatosis.
e
3.
Copper and zinc transport and storage in mammals
Contrary to popular belief, ceruloplasmin,
4
the principal copper-containing protein in plasma, is not involved in
copper transport. This is clearly underlined by the clinical observation that patients with aceruloplasminaemia
(i.e., lacking ceruloplasmin in their blood) have perfectly normal copper metabolism and homeostasis.
Copper is transported in plasma mostly by serum albumin with smaller amounts bound to low-molecular-weight
ligands like histidine. Likewise, zinc is mostly transported in plasma bound to proteins (albumin and
a
2
macroglobulin).
4. Ceruloplasmin, akin to Pirandello's Six Characters in Search of an Author, has long been a protein in search of a function. It is certainly
involved in tissue iron mobilisation, since systemic iron loading is found in the tissues of patients with aceruloplasminaemia and other
mutations of the ceruloplasmin gene.
