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Book Review |
Dean, College of Agriculture
California State Polytechnic University
Pomona, California
Ugo Testa. Boca Raton, FL: CRC Press, 2002.
As a single text on iron metabolism, this book is outstanding. Dr. Testa has taken the knowledge of his field, summarized the available literature of the essential research and provided a very readable account of iron metabolism. The quality of the writing is very good, with excellent use of figures and tables. The author cited more than 2700 current references, making it an valuable review. The result is an reference book that brings the reader up to date on the broad nature of this field.
Although the introduction is not identified as one of the chapters, it is as complete an overview of iron metabolism as is available at this time. The author provided a review of the area is a very systematic way with emphasis on the mammalian system. Bacteria and plants are noted as well. The mammalian processes are intricate, requiring genetic regulation of proteins involved in iron metabolism, absorption, transport and excretion, and specialization of the tissues involved. The author identifies 22 separate proteins involved in iron metabolism. Provided with such a thorough overview, the reader has a much better perspective about the interaction of the regulatory proteins as each chapter is read.
A few highlights from the chapters and a brief overview are included for the reader’s consideration. Iron absorption by intestinal enterocytes requires a ferric reductase in the brush border membrane to convert ferric iron to the more absorbable ferrous state (Chapter 1). The protein is called Dcytb (duodenal cytochrome b) and is up-regulated by all conditions associated with increased iron absorption. The ferrous iron is then absorbed by a divalent metal transporter (DCT1, divalent cation transporter, also called Nramp2, natural resistance-associated macrophage protein 1).
A microcytic anemia mouse (mk/mk) exhibits an autosomal recessive defect affecting absorption of dietary iron from the gut lumen into the intestinal epithelial cells due to a missense mutation in DCT1. The mutated DCT1 does not transport iron and is localized in the cytoplasmic compartment rather than the apical brush border membrane of the duodenal enterocyte. Nramp2 expression is restricted to the villus compartments of the duodenum. In iron-loaded animals, the Nramp2 is expressed at intracellular sites of enterocytes, whereas in iron depleted animals Nramp2 is expressed at cell membranes. Nramp2 appears to play a role in mediating absorption of non-transferrin bound iron at the erythroid cells. Erythroid cells contain both non-transferrin-bound iron (Nramp2) and transferrin bound iron (requiring transferrin receptors 1 and 2). The basolateral membrane of enterocytes contains a series of proteins called ferroportin (IREG1 and MTP1), which export iron from the villus cells. The iron regulatory element (IRE) occurs at the 5'-untranslated end of ferritin mRNA. Another sex-linked genetic defect in mice led to identification of an oxidase involved in iron oxidation and transport called hephaestin. The protein is a ceruloplasmin homologue found in the liver, blood and RES. Whether it functions as an iron exporter or an intracellular iron transporter remains to be clarified.
Hereditary hemochromatosis is an autosomal-recessive disease characterized by an increased absorption of dietary iron and a resultant accumulation of iron in parenchymal stores. The mutated gene encodes a transmembrane glycoprotein, HFE, which acts as a negative regulator of iron uptake (Chapters 5 and 7). Its regulatory effect occurs through interaction with transferrin receptor 1 (TfR1). The mutant HFE is unable to interact with the receptor. The normal HFE interacts with the Tf receptor 1 in a way that causes a structural change and a decrease Tf binding. The absence of HFE regulation results in increased iron uptake and storage. The potential mechanism(s) affecting iron absorption is(are) presented, involving HFE/Tf receptor 1 acting as a body iron sensor.
After transfer into the circulation, iron is complexed to transferrin (Tf) for transport to the tissues (Chapter 4). Tf is a glycoprotein with two homologous lobes, which can bind iron with a carbonate ion. Iron uptake from Tf is an essential pathway for sustaining erythropoiesis. Hypotransferrin mice die before weaning due to severe microcytic anemia, while total iron absorption and storage of iron in non-hematopoetic tissue is increased. Human atransferrinemia has a hereditary mutation in the transferrin gene, which results in a similar problem, hypochromic anemia and iron overload.
Transferrin receptors (TfR1 and TfR2) bind transferrin in most cells (Chapter 5). TfR1 is expressed in all cell types except mature erythrocytes. The receptor has three distinct regions, a protease-like domain, in intermediate helical domain and an apical domain. The three domains form a cleft for the binding of Tf. The complex formed by Tf and the TfR1 is internalized by endocytosis. Phosphorylation of Ser 24 in the cytosolic tail contributes to control of internalization. Some tissues express particularly high levels of TfR1 in erythroid cells and other rapidly growing cells. A transcriptional mechanism for controlling the up-regulation of TfR1 at the promoter sequence to the TfR1 gene is discussed. The availability of cellular iron appears to serve as a regulator at an IRE sequence stabilizing TfR1 RNA. Interestingly, after the release of iron from the TfR1/Tf complex, both TfR1 and Tf are recycled to the surface of the membrane. The entire cycle only takes three to five minutes. This cycle is very important in placental transfer of iron. In addition, a high level of expression occurs in some rapidly growing tumor cells.
The TfR2 receptor differs in its regulation from TfR1. The homology with TfR1 is about 66%, but the cytosolic tail is the highly divergent region. The TfR2 gene lacks the IRE sequence, suggesting it is not controlled by the IRP system. TfR2 is regulated by cell growth rate to a greater extent than iron levels. This receptor is not controlled by the HFE protein, indicating a twentyfold lower binding affinity from TfR1.
Soluble transferrin receptor (sTfR) lacks the first 100 amino acids, allowing it to circulate in the serum (Chapter 6). The formation of sTfR occurs by the protease clevage near the membrane surface. It appears that the sTfR increases with increased erythropoietic activity and declines as erythropoietic activity falls. In addition, as iron levels fall, sFtR levels increase.
Lactoferrin (Lf) is closely related to transferrin (Chapter 3). It has a similar structure, but is more stable, requiring a lower pH to release the iron. Lf is present in high concentrations in human milk and in early colostrum. It is also found in all mucosal secretions. Interestingly, the function of LF as an iron delivery protein may be less important than other activities such as anti-bacterial, anti-viral, and immune stimulation. Lf is bound by specific membrane sites, including the asialoglycoprotein receptor and low density lipoprotein receptor related protein (LPR), a non-LPR binding site that functions as a chylomicron remnant receptor. In addition, there are LfR expressed on activated T cells, platelets, megakaryocytes, dopaminergic neurons, mesencephalon microvessels and brain endothelial cells.
Ferritin is the cellular iron storage protein located in all tissues (Chapter 9). It is a 24 subunit protein that holds up to 4500 atoms of ferric iron in an inorganic complex. The heavy end (Fer-H) serves as the ferroxidase, while the light end (Fer-L) serves as the storage chamber. Overexpression of the Fer-H traps iron decreases the storage of iron and diminishes growth of cells. The regulation of ferritin occurs through both translational and transcriptional mechanisms. Translational controls are dependent on cellular levels of iron. With iron loading, the IRP protein is inactivated and does not bind to the ferritin mRNA, while during iron deprivation the binding of the IRP repressor protein to the 5'IRE untranslated region of the ferritin mRNA is induced with resultant repression of mRNA translation. Transcriptional mechanisms underly the stimulatory effects of heme on ferritin synthesis.
Additional factors covered in this text include delineation of iron-responsive elements (IREs) and iron regulatory proteins (IRPs). Heme oxygenase (HO1) is discussed in terms of heme degradation and the release of iron. Ceruloplasmin, a copper protein, serves as the serum oxidase to catalyse iron transport in and out of cells. Other proteins and their regulation are carefully characterized.
This text is a valuable reference, identifying the proteins involved in regulating iron metabolism. The book is a good book for nutrition and medical educators, an appropriate reader for graduate students and medical students and a useful synopsis for researchers working in the field.
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