Iron Functions

Oxygen transport and storage

Heme is an iron-containing compound found in a number of biologically important molecules. Hemoglobin and myoglobin are heme-containing proteins that are involved in the transport and storage of oxygen. Hemoglobin is the primary protein found in red blood cells and represents about two thirds of the body's iron. The vital role of hemoglobin in transporting oxygen from the lungs to the rest of the body is derived from its unique ability to acquire oxygen rapidly during the short time it spends in contact with the lungs and to release oxygen as needed during its circulation through the tissues. Myoglobin functions in the transport and short-term storage of oxygen in muscle cells, helping to match the supply of oxygen to the demand of working muscles .

Electron transport and energy metabolism

Cytochromes are heme-containing compounds that are critical to cellular energy production and therefore, life, through their roles in mitochondrial electron transport. They serve as electron carriers during the synthesis of ATP, the primary energy-storage compound in cells. Cytochrome P450 is a family of enzymes that functions in the metabolism of a number of important biological molecules, as well as the detoxification and metabolism of drugs and pollutants. Nonheme iron-containing enzymes, such as NADH dehydrogenase and succinate dehydrogenase, are also critical to energy metabolism.

Antioxidant and beneficial pro-oxidant functions

Catalase and peroxidases are heme-containing enzymes that protect cells against the accumulation of hydrogen peroxide, a potentially damaging reactive oxygen species (ROS), by catalyzing a reaction that converts hydrogen peroxide to to water and oxygen. As part of the immune response, some white blood cells engulf bacteria and expose them to ROS in order to kill them. The synthesis of one such ROS, hypochlorous acid, by neutrophils is catalyzed by the heme-containing enzyme myeloperoxidase.

Oxygen sensing

Inadequate oxygen (hypoxia), such as that experienced by those who live at high altitudes or those with chronic lung disease, induces compensatory physiologic responses, including increased red blood cell formation, increased blood vessel growth (angiogenesis) and increased production of enzymes utilized in anaerobic metabolism. Under hypoxic conditions transcription factors, known as hypoxia inducible factors (HIF), bind to response elements in genes that encode various proteins involved in compensatory responses to hypoxia and increase their synthesis. Recent research indicates that an iron-dependent prolyl hydroxylase enzyme plays a critical role in regulating HIF and consequently, physiologic responses to hypoxia. When cellular oxygen tension is adequate, newly synthesized HIFa subunits are modified by a prolyl hydroxylase enzyme in an iron-dependent process that targets HIFa for rapid degradation. When cellular oxygen tension drops below a critical threshold, prolyl hydroxylase can no longer target HIFa for degradation, allowing HIFa to bind to HIFb and form an active transcription factor that is able to enter the nucleus and bind to specific response elements on genes.

DNA synthesis

Ribonucleotide reductase is an iron-dependent enzyme that is required for DNA synthesis. Thus, iron is required for a number of vital functions, including growth, reproduction, healing, and immune function.

Regulation of intracellular iron

Iron response elements are short sequences of nucleotides found in the messenger RNA (mRNA) that codes for key proteins in the regulation of iron storage and metabolism. Iron regulatory proteins (IRP) can bind to iron response elements and affect mRNA translation, thereby regulating the synthesis of specific proteins. It has been proposed that when the iron supply is high, more iron binds to IRPs and prevents them from binding to iron response elements on mRNA. When the iron supply is low, less iron binds to IRPs, allowing increased binding of iron response elements. Thus, when less iron is available, translation of mRNA that codes for the iron storage protein, ferritin, is reduced because iron is not available for storage. Translation of mRNA that codes for the key regulatory enzyme of heme synthesis in immature red blood cells is also reduced to conserve iron. In contrast, IRP binding to iron response elements in mRNA that codes for transferrin receptors inhibits mRNA degradation, resulting in increased synthesis of transferrin receptors and increased iron transport to cells.

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