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Iron is a vital element for the maintenance and survival of life. A few key interactions mediated by iron include oxygen transfer via haemoglobin in vertebrates and electron transfer in cytochromes. It is a key component of enzymes such as glutamate synthase and ribonucleotide reductase. Free Iron in cells can cause havoc by accelerating hazardous free radical reactions. A major fraction of the vertebrate iron requirements are met by the recycling of iron present in red blood cells. A system that ensures homeostasis of a critical component such as iron must store it in a non-toxic form and provide layered control strategies for the organism to regulate it.

Iron Cycle
Key features of a system for metabolite regulation are

Transportation : The blood plasma protein transferrin performs this role in vertebrates

Assimilation : A variety of mechanisms for iron uptake by cells are being examined such as transferrin receptor (TfR) mediated endocytosis, TfR independent uptake (via pinocytosis)  and reductive import. Inside cells, Iron is released from transferrin by changes in pH and putative reductive mechanisms.

Storage : Subsequently, Iron enters a labile intra-cellular pool that supplies it for biochemical reactions in the cell. This region has been very poorly characterized and a variety of candidates have been proposed for the same. The cellular iron stores are proteins such as ferritin and hemosiderin. The mechanism of storage and retrieval from them is still uncertain.

Here, the focus will be on regulatory mechanisms involved in the expression of transferrin and ferritin.

Structural Features
Transferrin is a monomeric, biolobar protein that is glycosylated that is considered to be a product of gene duplication. Two molecules of Fe+3 can bind to the protein concomitantly with anionic radicals such as carbonate or bicarbonate.



Ferritin is a globular protein that consists of an inorganic hydrated ferric oxide core encapsulated by a protein shell that solubilizes this construct. Phosphate residues in the core stabilize it and mediate protein-core interactions.

Control Mechanisms
Control mechanisms in the Transferrin - Ferritin pathway are layered in nature – transcriptional and translational levels of control exist. They are built upon specific recognition by molecules and regulatory mechanisms such as phosphorylation and m-RNA stability.

Growth Stage Dependence

Erythroid Cells undergoing differentiation have a higher proportion of Transferrin Receptors than their precursors. Luekemic cells show the opposite effect.

Post-Transcriptional Layer – Protein mRNA interactions

In non-Erythroid cells this interaction is mediated by Iron Regulatory Proteins (IRPs 1 and 2) that interact with stem loop structures in mRNA called Iron Responsive Elements (IREs). These are present on the 5’ UTR of the ferritin mRNA and 3’ UTR of transferrin receptor (TfR) mRNA.



RNA binding activity of IRP1 and iron levels within the cell are reciprocally correlated to each other. This is due to the formation of a tetrameric Fe-S complex under ample iron supply. The binding of IRP1 to IRE of ferritin represses mRNA translation while the binding to IRE of TfR increases mRNA stability by preventing restriction enzyme mediated digestion.

Hence, under conditions of iron starvation of cells, they will try to express more Transferrin receptors to efficiently sap up the iron in the exterior environment. When intracellular iron levels are high, cells will stop uptake of iron by Transferrin and try to store the excess amount efficiently.

Increased activity via phosphorylation has also been proposed, hinting at possibility of hormones acting as control elements. The IREs of IRP1 and IRP2 are distinct. Response to iron is same in both cases. However, the molecular mechanism in the case of IRP2 is iron induced protein breakdown.

Transcription Layer 

There is a different layer of control in the case of erythroid cells, the transcriptional level. In this scenario, mRNA half life is insensitive to Iron levels. Zinc finger transcrition factor (TF) binding protein domains flank the exons in the TfR gene. These may be positively regulated by presence of Zn+2 or Fe+2 (positive feedback loop). Studies also indicate the presence of an activator protein binding site that can be positively be upregulated by TFs such as NF-E2.

The exact mechanism of metabolic regulation is specific and varies among different cell types such as cells of the ]placenta and that of the blood brain barrier.

NO mediated

Nitric Oxide is a second messenger produced by the action of NO synthase on L-arginine. NO modulates the activities of a large number of proteins such as guanylate cyclase and aconitase, by interacting with iron containing groups.

The outcome of the interaction of Nitrogen Oxides with the iron regulatory mechanism is highly sensitive to the redox state of nitrogen. The interactions can be mediated by bonding with the Fe-S cluster or S-nitrosylation of the –SH groups of cysteine. Indirect impact on the control of iron can also be mediated via NO activated phosphorylases/kinases.

Siderophores - An Analogue
Siderophores are iron binding compounds that are secreted by an array of organisms that include bacteria, fungi and plants. Their interaction with iron can be mediated by hydroxamate or catechol residues. Specific receptors for these compounds exist on the cell surface. Mechanisms of release of bound iron include reduction, hydrolysis and ligand exchange. Regulatory mechanisms are type specific. However, synthesis pathways can be differentiated on the basis of dependence on mRNA, into non-ribosomal and ribosomal peptides. Its production is regulated by intra-cellular iron pools. However, the process is highly energy intensive.