The Iron-Sulfur Cluster of Iron Regulatory Protein 1 Modulates the Accessibility of RNA Binding and Phosphorylation Sites†

Biochemistry ◽  
1997 ◽  
Vol 36 (13) ◽  
pp. 3950-3958 ◽  
Author(s):  
Kevin L. Schalinske ◽  
Sheila A. Anderson ◽  
Polygena T. Tuazon ◽  
Opal S. Chen ◽  
M. Claire Kennedy ◽  
...  
Keyword(s):  
Rna Binding ◽  
Regulatory Protein ◽  
Phosphorylation Sites ◽  
Iron Regulatory Protein ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Iron Regulatory Protein 1

Peroxynitrite and Nitric Oxide Differently Target the Iron−Sulfur Cluster and Amino Acid Residues of Human Iron Regulatory Protein 1†

Biochemistry ◽  
2003 ◽  
Vol 42 (25) ◽  
pp. 7648-7654 ◽  
Author(s):  
Emmanuelle Soum ◽  
Xavier Brazzolotto ◽  
Charilaos Goussias ◽  
Cécile Bouton ◽  
Jean-Marc Moulis ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Amino Acid ◽  
Regulatory Protein ◽  
Iron Regulatory Protein ◽  
Amino Acid Residues ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Iron Regulatory Protein 1

Human Cytosolic Iron Regulatory Protein 1 Contains a Linear Iron−Sulfur Cluster

2001 ◽  
Vol 123 (41) ◽  
pp. 10121-10122 ◽  
Author(s):  
Jürgen Gailer ◽  
Graham N. George ◽  
Ingrid J. Pickering ◽  
Roger C. Prince ◽  
Peter Kohlhepp ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Iron Regulatory Protein ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Iron Regulatory Protein 1

Multiple Causes of Iron Overload In Tissues, Cells and Subcellular Compartments

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Tracey Rouault
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract SCI-27 Iron metabolism is regulated in mammals to assure that adequate iron is delivered to the hematopoietic system to support erythropoiesis. In systemic iron metabolism, regulation of both iron uptake from the diet and release from erythrophagocytosing macrophages is coordinated by action of the peptide hormone, hepcidin, which inhibits activity of the iron exporter, ferroportin. In general, high expression of hepcidin diminishes duodenal iron uptake and reduces macrophage iron release, a combination observed in the anemia of chronic disease. Low expression of hepcidin, which is synthesized by hepatocytes and influenced by transferrin receptor 2, HFE, hemojuvelin and bone morphogenetic receptors, facilitates iron uptake. Mutations affecting genes in the hepcidin pathway cause hemochromatosis, characterized by systemic iron overload that affects mainly hepatocytes and cardiac myocytes, but spares the CNS. In contrast, there are several degenerative diseases of the CNS in which neuronal iron overload is prominent and may play a causal role. The underlying pathophysiologies of neuronal brain iron accumulation syndromes remain unclear, even though several causal genes have been identified, including pantothenate kinase 2 and aceruloplasminemia. In some cases, increased iron may be inaccessible, and cells may suffer from functional iron insufficiency, as we propose for animals that lack iron regulatory protein 2. It is also possible that errors in subcellular iron metabolism can lead to mitochondrial iron overload and concomitant cytosolic iron deficiency, a combination observed in Friedreich ataxia, ISCU myopathy, and the sideroblastic anemia caused by glutaredoxin 5 deficiency. In each of these diseases, mitochondrial iron-sulfur cluster assembly is impaired, and it appears that normal regulation of mitochondrial iron homeostasis depends on intact iron-sulfur cluster assembly. Finally, in heme oxygenase 1 deficient animals, macrophages in the spleen and liver die upon erythrophagocytosis, and failure to normally metabolize heme leads to shift of heme iron to proximal tubules and macrophages of the kidney. Thus, treatment of “iron overload” must depend on the underlying causes, and removal of iron is appropriate in hemochromatosis, but more specific forms of therapy are needed for other forms of iron overload. 1. Ye, H. & Rouault, T. A. (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49, 4945–4956. 2. Zhang, A. S. & Enns, C. A. (2009). Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program 207–214. 3. Ye, H., Jeong, S. Y., Ghosh, M. C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C. & Rouault, T. A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749–1761. 4. Ghosh, M. C., Tong, W. H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M. C., Mitchell, J. B. & Rouault, T. A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028–12033. 5. Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. (2010). Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869. Disclosures: No relevant conflicts of interest to declare.

A disease-modifying treatment for Alzheimer’s disease: focus on the trans-sulfuration pathway

2020 ◽  
Vol 31 (3) ◽  
pp. 319-334
Author(s):  
Thomas Berry ◽  
Eid Abohamza ◽  
Ahmed A. Moustafa
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Citric Acid ◽  
Citric Acid Cycle ◽  
Regulatory Protein ◽  
Iron Sulfur Cluster ◽  
Acid Cycle ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Low Activity

AbstractHigh homocysteine levels in Alzheimer’s disease (AD) result from low activity of the trans-sulfuration pathway. Glutathione levels are also low in AD. L-cysteine is required for the synthesis of glutathione. The synthesis of coenzyme A (CoA) requires L-cysteine, which is synthesized via the trans-sulfuration pathway. CoA is required for the synthesis of acetylcholine and appropriate cholinergic neurotransmission. L-cysteine is required for the synthesis of molybdenum-containing proteins. Sulfite oxidase (SUOX), which is a molybdenum-containing protein, could be dysregulated in AD. SUOX detoxifies the sulfites. Glutaminergic neurotransmission could be dysregulated in AD due to low levels of SUOX and high levels of sulfites. L-cysteine provides sulfur for iron-sulfur clusters. Oxidative phosphorylation (OXPHOS) is heavily dependent on iron-sulfur proteins. The decrease in OXPHOS seen in AD could be due to dysregulations of the trans-sulfuration pathway. There is a decrease in aconitase 1 (ACO1) in AD. ACO1 is an iron-sulfur enzyme in the citric acid cycle that upon loss of an iron-sulfur cluster converts to iron regulatory protein 1 (IRP1). With the dysregulation of iron-sulfur cluster formation ACO1 will convert to IRP1 which will decrease the 2-oxglutarate synthesis dysregulating the citric acid cycle and also dysregulating iron metabolism. Selenomethionine is also metabolized by the trans-sulfuration pathway. With the low activity of the trans-sulfuration pathway in AD selenoproteins will be dysregulated in AD. Dysregulation of selenoproteins could lead to oxidant stress in AD. In this article, we propose a novel treatment for AD that addresses dysregulations resulting from low activity of the trans-sulfuration pathway and low L-cysteine.

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