Iron Regulatory Proteins 1 and

Effect of Al on Iron Regulatory Protein-1 and -2 in Mammalian Cells... 

Iron Regulatory Proteins 1 and 2 (IRPl and 2) are Important Cytosolic Iron Sensors that Regulate Expression of Ferritin, Transferrin Receptor and Other Iron Metabolism Proteins... 

Henderson, B., Menotti, E., and Kuhn, L. C. (1996). Iron regulatory proteins 1 and 2 bind distinct sites of RNA target sequences. J. Biol. Chem. 271,4900-4908. 

Castro, L.A., Robalinho, R.L., Cayota, A., Meneghini, R., Radi, R. (1998). Nitric oxide and peroxynitrite-dependent aconitase inactivation and iron-regulatory protein-1 activation in mammalian fibroblasts. Arch. Biochem. Biophys. 359 215-24. 

Toth, I. Yuan, L. Rogers, J. T. Boyce, H. Bridges, K. R. Hypoxia alters iron-regulatory protein-1 binding capacity and modulates cellular iron homeostasis in human hepatoma and erythroleukemia cells. J. Biol. Chem. 274 4467-4473 1999. 

Soum E, Brazzolotto X et al (2003) Peroxynitrite and nitric oxide differently target the iron-sulfur cluster and ammo acid residues of human Iron regulatory protein 1. Biochemistry 42 7648-7654... 

How Does NO and H2O2 Affect the Iron Regulatory Proteins IRP-1 and IRP-2... 

In the EPR of mammalian cells, we do not see much in addition to the signals from the respiratory complexes. The enzyme aconitase from the citric-acid cycle can be detected, and also the protein cytoplasmic aconitase, later identified as the mRNA translation regulatory factor iron regulatory protein IRP-1, which actually started its career in biochemistry as an EPR signal that could not be assigned to the respiratory chain (Kennedy et al. 1992). 

Iron regulatory proteins (IRPs) regulate the cellular iron level in mammalian cells. IRPs are known as cytosol mRNA binding proteins which control the stability or the translation rate of mRNAs of iron metabolism-related proteins such as TfR, ferritin, and 5-aminolevulinic acid synthetase in response to the availability of cellular iron [19-21] after uptake [5]. The regulatory mechanism involves the interaction between the iron-responsive element (IRE) in the 3 or 5 untranslated regions of the transcripts and cytosolic IRPs (IRP-1 and -2). IRP-1 is an iron-sulfur (Fe-S) protein with aconitase activity containing a cubane 4Fe-4S cluster. When Fe is replete, IRP-1 prevails in a 4Fe-4S form as a holo-form and is an active cytoplasmic aconitase. As shown in Fig. 3, when Fe is deplete, it readily loses one Fe from the fourth labile Fe in the Fe-S cluster to become a 3Fe-4S cluster and in this state has little enzymatic activity [22, 23]. 

The stmctural, electronic, biological, and magnetic properties of iron sulfur clusters in metalloproteins has been reviewed focussing particularly on [4Fe-4S ]"+ (n = 1-3) centres, and on synthetic [Fe3S4] and heterometallic [MFe3 S4] clusters. The chemistry and properties of aconitase have been reviewed in the context of its spectroscopic properties, structure, mechanistic function, and its relationship to the iron-regulatory protein. ... 

Total-body iron of a 70-kg adult is about 4.2-4A g. The distribution of iron in various body compartments is given in Table 29-1. The key players of iron metabolism include iron-responsive elements of appropriate mRNAs, iron regulatory proteins divalent metal transporter 1, major histocompatibility complex (MHC) class I-like protein designated as HFE protein, d2-microglobulin, transferrin, transferrin receptor, and ferritin. 

Fig. 1.45 Regulation of the stability of the mRNA ofthe transferrin receptor by Fe3+. The translation of the mRNA ofthe transferrin receptor (TFR) is subject to regulation by the Fe concentration. Fe exerts its regulatory effect via the iron regulatory protein typel (IRP1). The IRP1 binds to a control segment at the 3 terminal region ofthe TFR mRNA, known as the iron responsive element (IRE). Binding of IRP1 to a hairpin structure of the IRE stabilizes the mRNA ofthe transferrin receptor and...

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