Iron is a key constituent of many human proteins, including hemoglobin, myoglobin, the cytochrome P450 group of enzymes, numerous components of the electron transport chain, and ribonucleotide reductase, which catalyzes the con version of ribonucleotides into deoxyribonucleotides. Body iron, which is distributed as shown in Table 1, is highly conserved. A healthy adult loses only about 1 to 1.5 mg (< 0.05%) of their 3 to 4 g of body iron each day. However, an adult premenopausal female can experience iron deficiency due to blood loss during menstruation.

Table1. Distribution of Iron in a 70-kg Adult Male ^a

Enterocytes can absorb dietary iron in its free, ferrous Fe2+, form, or as heme. Absorption of non-heme iron by enterocytes of the proximal duodenum is a highly regulated process (Figure 1). The transfer of iron across the apical membrane of the enterocytes is mediated via the divalent metal transporter 1 (DMT1 or SLC11A2), a transporter that also conveys Mn2+, Co2+, Zn2+, Cu2+, and Pb2+. Since DMT1 is specific for divalent metal ions, free ferric iron (Fe3+) must be converted to its ferrous form (Fe2+) by ingested reducing agents such as vitamin C, or enzymatically by a brush border membrane-bound ferrireductase, duodenal cytochrome b (Dcytb). Once absorbed, heme-bound iron is released by the enzymatic action of heme oxygenase.

Fig1. Non-heme iron transport in enterocytes. Ferric iron is reduced to the ferrous form by a luminal ferrireductase, duodenal cytochrome b (Dcytb). Ferrous iron is transported into the enterocyte via divalent metal transporter1 (DMT1). Within the enterocyte, iron is either stored as ferritin, or transported out of the cell by ferroportin (Fp). Ferrous iron is oxidized to its ferric form by hephaestin. The ferric iron is then bound by transferrin for transport by the blood to various sites in the body.

On entering the enterocytes, iron can either be stored bound to the iron-storage proteinferritin or transferred across the basolateral membrane by the iron exporter protein ferroportin, also known as iron-regulated protein 1 (IREG1 or SLC40A1). In the plasma, iron is transported in the Fe3+ form bound to the transport protein, transferrin. Hephaestin, a copper-containing ferroxidase homologous to ceruloplasmin, oxidizes Fe2+ to Fe3+ prior to export. Any excess ferritin-bound iron remaining in the enterocytes is disposed of when they are sloughed off into the gut lumen.

Ferritin Can Bind Thousands of Fe3+ Atoms

The human body can typically store up to 1 g of iron, the vast majority of which is bound to ferritin. Ferritin (MW 440 kDa) forms a hollow ball composed of two-dozen ≈19 to 21 kDa polypeptide subunits that can encapsulate as many as 3000 to 4500 ferric atoms. Ferritin subunits may be of the H (heavy) or the L (light) type. The H-subunit possesses ferroxidase activity, which is required for iron-loading of ferritin. The L-subunit is proposed to play a role in ferritin nucleation and stabilization. Normally, a small amount of ferritin is present in human plasma (50-200 μg/dL) proportionate to the total stores of iron in the body. While it is not known whether the ferritin in plasma is derived from damaged cells or secretion from healthy ones, plasma ferritin levels provide a useful indicator of body iron stores. Hemosiderin, a partly degraded form of ferritin, also may appear in tissues under conditions of iron overload (hemosiderosis).

Transferrin Shuttles Iron to Where It Is Needed

The toxicity of free iron is largely a consequence of its ability to induce the formation of damaging reactive oxygen species (Figure 2). Living organisms protect themselves against iron’s potential toxicity by employing specialized storage and transport proteins, and transporting iron in its less reactive, Fe3+, state. In humans, Fe3+ is transported through the circulation bound to transferrin (Tf), a glycoprotein synthesized by the liver. This β1-globulin has a molecular mass of approximately 76 kDa and contains two high-affinity binding sites for Fe3+. Glycosylation of transferrin is impaired in congenital disorders of glycosylation or in chronic alcoholism, a condition for which the presence of carbohydrate-deficient transferrin (CDT) is sometimes used as a biomarker.

Fig2. The Fenton reaction.Free iron is extremely toxic as it can catalyze the formation of hydroxyl radical (OH•) from hydro gen peroxide. The hydroxyl radical is a transient but highly reactive species and that oxidize cellular macromolecules resulting in tissue damage.

The concentration of Tf in plasma is approximately 300 mg/dL, sufficient to carry a total of approximately 300 μg of iron per deciliter of plasma, which represents the total iron binding capacity (TIBC) of plasma. Typically, about 30% of the iron-binding sites in transferrin are occupied. Occupancy can decrease to less than 16% during severe iron deficiency and may increase to more than 45% in iron overload conditions.

The Transferrin Cycle Facilitates Cellular Uptake of Iron

For the delivery of transported iron, the recipient cell must bind circulating transferrin via a cell surface receptor, the transferrin receptor 1 (TfR1). The receptor-transferrin com plex is then internalized by receptor-mediated endocytosis into late endosomes. The bound iron is then released as late endosomes become acidified and is trans ported to the cytoplasm by DMT1. Still bound to the transferrin receptor, the iron-free or apotransferrin receptor (apoTf) is returned by the endosome to the cell surface, where it dis sociates from the receptor and reenters the plasma ready to bind more iron. This recycling process is called the transferrin cycle (Figure 3).

Fig3. The transferrin cycle.Holotransferrin (Tf-Fe) binds to transferrin receptor 1 (TfR1) present in clathrin-coated pits on the cell surface. The TfR1–Tf-Fe complex is endocytosed and the endocytic vesicles fuse to form early endosomes. The early endosomes mature in to late endosomes, which have a low internal pH. These acidic conditions cause the release of iron from transferrin. The resulting apotransferrin (apoTf) remains bound to TfR1. Ferric iron is converted to its ferrous form by the ferrireductase, Steap 3, and is then transported to the cytosol via DMT1. The TfR1-apoTf complex then is recycled back to the cell surface. At the cell surface, apoTf is released from TFR1. TfR1 then binds to new Tf-Fe. This completes the transferrin cycle.

While TfR1 is found on the surface of most cells, the homologous transferrin receptor 2 (TfR2) is encountered primarily on the surface of hepatocytes and the crypt cells of the small intestine. The affinity of TfR2 for transferrin is much lower than that of TfR1, optimizing the former as a sensor, rather than an importer, for iron.

Oxidation by Ceruloplasmin Is a Key Feature of the Iron Cycle

Macrophages play a key role in the turnover of red blood cells. Following phagocytosis and digestion via lysosomal hydro lases, the free iron is expelled largely in the ferrous, Fe2+, state. In order to be recovered via the transferrin cycle, this iron must be oxidized to the ferric, Fe3+, state by the ferroxidase ceruloplasmin, a 160-kDa α2-globulin synthesized in the liver. Cerruloplasm carries out this oxidation using six, catalytically essential, copper atoms whose presence renders it the major copper-containing protein in plasma.

Deficiencies in Ceruloplasmin Perturb Iron Homeostasis

Ceruloplasmin deficiency can arise from genetic causes as well as a lack of dietary copper, an essential micronutrient. When adequate quantities of catalytically functional ceruloplasmin are lacking, the body’s ability to recycle Fe2+ becomes impaired, leading to iron accumulation in tissues. While per sons suffering from hypoceruloplasmenia, a genetically heritable condition in which ceruloplasmin levels are roughly 50% of normal, generally display no clinical abnormalities, genetic mutations that abolish the ferroxidase activity of ceruloplasmin, aceruloplasminemia, can have severe physiologic con sequences. If left untreated, the progressive accumulation of iron in pancreatic islet cells and basal ganglia eventually leads to the development of insulin-dependent diabetes and neuro logic degeneration that may manifest as dementia, dysarthria, and dystonia.

Ceruloplasmin Levels Decrease in Wilson Disease

 In Wilson disease, a mutation in the gene for acopper-binding P-type ATPase (ATP7B protein) blocks the excretion of excess copper in the bile. As a consequence, copper accumulates in the liver, brain, kidney, and red blood cells. Paradoxically, rising levels of copper within the liver apparently interferes with the incorporation of this metal into newly synthesized ceruloplasmin polypeptides (apoceruloplasm) leading to a fall in plasma ceruloplasmin levels. If left untreated, patients suffering from this form of copper toxicosis may develop hemolytic anemia or chronic liver disease (cirrhosis and hepatitis), while the accumulation of copper in the basal ganglia can lead to neurologic symptoms. Wilson disease can be treated by limiting the dietary intake of copper while concurrently depleting any excess copper already present by the regular administration of penicillamine, a copper chelating agent that is excreted in the urine.

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