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RESEARCH INTERESTS

My research interests are in the general area of iron protein biochemistry. The goal is to elucidate the structure-function relationships and better understand the role of these crucial proteins in the regulation of cellular iron homeostasis.  Proteins such as human transferrin, cytoplasmic and mitochondrial ferritins of different origins, human and bacterial frataxin are being investigated.  The hope is to generate new knowledge that is essential for the rational development of new treatments for iron overload diseases and other defects in iron metabolism.

Iron is a vital element for almost all living organisms due to its essential role in numerous metabolic processes. However, excess free iron has been implicated in neurodegenerative diseases, apoptosis, and also in the generation of harmful free radicals that cause damage to membranes, proteins and nucleic acids.  The low solubility of iron at physiological conditions (~ 10-18 M) has compelled living  organisms to adapt efficient iron transport and storage mechanisms, one of which is transferrin, a plasma transport protein which carries iron in the circulation from the gut to the bone marrow and other tissues for the synthesis of hemoglobin and other iron containing proteins.

The iron-transport protein "Transferrin"
Transferrin is a naturally occurring metal chelating protein that is responsible for the transport and donation of Fe to cells and tissues where it is utilized by many iron-containing enzymes.  It is a bilobale protein (C- and N-lobes) with two high affinity Fe(III) binding sites.  In each lobe iron is bound to two tyrosines, one aspartate, one histidine and a bidentate synergistic carbonate anion.  The iron loaded transferrin (holotransferrin) delivers its content of iron by endocytosis after interaction with the transferrin receptor on the cell membrane.   Holotransferrin has a high affinity for its receptor while Fe-free transferrin does not, and this has important physiological implications in terms of the mechanism of transferrin uptake by cells  

By binding iron tightly, transferrin helps to avoid the formation of free radicals reactions catalyzed by iron.  These reactions are implicated in the formation of various cancers, arteriosclerosis, arthritis, and liver and heart diseases.  Transferrin is also the target of chelation therapy used to treat individuals with diseases of iron overload such as “Thalassemia” and “Hemochromatosis”, the most common genetic disorder in this country, affecting 1 out of 200 individuals.

Receptor Transferrin Endocytosis


                                           
The iron-storage protein "Ferritin"

Another mechanism for overcoming iron toxicity and solubility is ferritin, a ubiquitous iron storage, detoxification and biomineralizing protein found highly conserved in species from bacteria to plants to humans. In mammals, ferritins are composed of 24 subunits of two types, H and L.  These subunits have complementary roles in iron oxidation and mineralization: the H-chain subunit has ferroxidase activity associated with a di-iron binding center that is responsible for the rapid oxidation of Fe2+ to Fe3+:

2 Fe2+ + O2 + 4 H2O  »  2 FeOOH(core) + H2O2 + 4 H+ 
4 Fe2+ + O2 + 6 H2O  »  4 FeOOH(core) + 8 H+ 
2 Fe2+ + H2O2 + 2 H2O  »  2 FeOOH(core) + 4 H+

Ferritin-Protein shell


whereas the L-chain subunit appears to provide efficient sites for iron nucleation and mineralization. The distribution and composition of ferritins in mammals is organ- dependent, emphasizing the importance of the L-chain in mineral core nucleation and the H- chain in rapid iron oxidation and detoxification.  For instance, ferritins in iron storage organs such as liver and spleen are L-chain rich whereas those from heart and red blood cells are H-chain rich.










Ferroxidation mechanism in the recombinant human H-chain ferritin


 





FRATAXIN RESEARCH
Another are of research involves the newly discovered mitochondrial protein frataxin, whose deficiency causes Friedreich’s ataxia, a life- shortening, debilitating and rare genetic neurodegenerative  disorder. Onset of symptoms usually occurs between the ages of 5 and 15 and includes muscle weakness, loss of coordination in the arms and legs, impairment of vision, hearing and speech, aggressive scoliosis (curvature of the spine), diabetes, and a serious heart condition. Most patients find themselves confined to a wheelchair by their late teens or early twenties. There is no cure! Most childhood onset patients with this disease die in early adulthood.  Our goal is to better understand the role of this protein in iron metabolism and define its exact biological function with the hope to find treatments and a cure for this relentless and devastating disease.                     Bacterial Frataxin (CyaY)                     













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