Iron Metabolism | Zoology Optional Notes for UPSC PDF Download

Introduction

• Various tests have evolved for evaluating iron metabolism and stores, with blood ferritin measurement largely replacing bone marrow examination. Modern diagnostics include advanced assessments such as transferrin (Tf) and soluble transferrin receptor (sTfr) measurements, along with hepcidin, reflecting dynamic iron metabolism. Additionally, genetic variations in proteins related to iron metabolism aid in diagnosing iron metabolic disorders.
• While genomic and proteomic studies on iron metabolism have been conducted in organisms like tomato and Arabidopsis, similar studies in humans are limited. In plant biology, the term 'ferromics' is coined, encompassing research on iron deficiency in plant. 'Ironomics' and 'ironome' have been used to describe iron metabolism in Yersinia pestis biotypes and within cells and organelles, respectively . This review focuses on key physiological pathways in human iron metabolism, particularly relevant for transfusion medicine specialists managing donors.

Iron Metabolism and Proteins

The understanding of iron trafficking and metabolism has significantly advanced in the past two decades. 

• Numerous proteins play crucial roles in iron metabolism, as outlined in comprehensive reviews. Ferritin and transferrin (Tf) are essential for transporting iron in the blood, while peptides like iron regulatory proteins (IRPs), hepcidin, and matriptase (Mt2) contribute to iron regulation at different levels. 
• Proteins such as divalent metal transporter-1 (DMT1), ferroportin (FPN1), and transferrin receptors (Tfrs), along with ferroxidases like duodenal cytochrome B, ceruloplasmin (Cp), and heme carrier protein (HCP1), are involved in cellular membrane iron transportation . 
• Other proteins, including myoglobin (Mb), hemoglobin (Hb), and various enzymes, represent the end products of iron metabolism, as they rely on iron for their functions.

Hepcidin: The Queen of 'Ironomics'

A comprehensive review of iron metabolism would be incomplete without highlighting the pivotal role of hepcidin and acknowledging the groundbreaking contributions of Tomas Ganz and Elisabeta Nemeth. Their collaborative efforts, spanning from 2003 to 2013, resulted in the publication of nearly 100 scientific papers, with more than half featuring the keyword 'hepcidin.' 

Hepcidin, akin to the Queen of the Night in Mozart's opera 'The Magic Flute,' emerges as a central figure in the intricate orchestration of ironomics.

• Hepcidin is a 25-amino acid peptide hormone primarily synthesized by hepatocytes. Encoded by the HAMP gene, hepcidin is derived from the precursor protein pro-hepcidin through a cleavage process. The regulation of hepcidin synthesis in response to iron levels involves various mechanisms. 
• and pathological conditions, such as the release of bone morphogenetic protein (BMP), hypoxia, and processes related to endocrine, metabolic, and inflammatory factors, contribute to the modulation of hepcidin biosynthesis. This intricate regulation, in turn, governs the availability of iron for erythropoiesis by adapting iron absorption and recirculation

Iron Regulatory Proteins

Iron serves essential functions in various cell types, participating in processes such as iron supply and storage. Differentiated cells are involved in exporting iron, including enterocytes responsible for absorbing iron from digested food, macrophages and hepatocytes involved in iron recycling based on demand, and placental syncytiotrophoblast cells facilitating iron transport into the fetal circulation. Maintaining cellular iron homeostasis is orchestrated by Iron Regulatory Proteins (IRP1 and IRP2), as extensively reviewed.

The mechanism involves IRPs binding to Iron-Responsive Elements (IREs) situated in the untranslated regions of genes and mRNAs encoding proteins integral to iron uptake, storage, utilization, and export. The IRP/IRE system intricately regulates the synthesis and suppression of numerous proteins, playing a crucial role in the finely tuned network of 'ironomics' pathways.

Iron Distribution in the Body

In males, the body contains approximately 4,000 mg of iron. Among this, 2,500 mg resides within erythrocytes, 1,000 mg is stored in splenic and hepatic macrophages, and the remainder is distributed across various iron-containing proteins like myoglobin (Mb), cytochromes, and other ferroproteins. Only about 3 mg is bound to plasma transferrin (Tf), constituting the mobile iron compartment responsible for supplying the diverse intracellular iron stores.

Iron in the Food: Unusual Aspects

Iron, despite being the most abundant element on Earth, poses potential toxicity to living cells. Paradoxically, it has poor bioavailability, prompting efforts to address widespread iron deficiency through food fortification, particularly in staple foods like rice. While iron is essential for human nutrition, rice and many cereals inherently contain low iron levels due to losses during grain processing. Populations heavily reliant on monotonous cereal-based diets are especially susceptible to iron deficiency, affecting approximately two billion people.

• Conventional food fortification programs have faced challenges in achieving widespread success. An alternative solution is iron biofortification, involving various approaches such as conventional breeding and directed genetic modification, which represents a rapid means to develop iron-rich rice plants. 
• Another approach involves biofortifying crops, which can be achieved through the application of mineral fertilizers, enhancing the solubilization and mobilization of mineral elements in the soil, and developing crops with increased abilities to acquire and accumulate mineral elements in edible tissues. 
• Transgenic approaches have been employed to create high-iron rice, incorporating the soybean ferritin gene under the control of the endosperm-specific glutelin promoter into the genome of the Indica rice. 
• However, skepticism about transgenic food remains widespread, emphasizing the need to improve our understanding of the iron content in common foods and the factors influencing its absorption .
• From a hematologist's perspective, universal iron fortification of food may present challenges, especially for individuals with conditions like hemochromatosis and other iron-loading diseases. While some consider iron fortification a viable strategy against iron deficiency, certain health authorities have chosen to abandon it. For a more in-depth exploration of iron fortification, iron-rich foods, and related topics, readers are encouraged to refer to recent reviews published in 2012.