Current Students | Ali Shawki
Iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile iron overload associated with conditions like hereditary hemochromatosis, thalassemia, or sickle-cell disease poses a serious threat to many other individuals.
Divalent metal-ion transporter-1 (DMT1) is indispensable for iron homeostasis. It is the front-line, primary route of uptake in the intestine. DMT1 is also responsible for mobilization of iron from the endosome to cytosol, a crucial step in the transferrin-associated uptake of iron in erythroid precursor cells. Meanwhile, ferroportin is responsible for export of iron from enterocytes and macrophages.
I am interested in the molecular physiology of iron transport, focusing on the substrate profile and molecular mechanisms of the divalent metal-ion transporter DMT1 and ferroportin. One of my projects is to study the molecular impact of rare mutations in human DMT1 associated with disease phenotypes as a way to probe the structure-function of this protein.
I am also interested in the inhibition of DMT1 mediated iron transport. Recently, I have discovered that Ca2+ is a non-competitive inhibitor of DMT1 which could at least in part, provide the molecular basis to the observation that dietary calcium inhibits iron absorption. Calcium inhibition of DMT1 may be taken into consideration when developing strategies for improved nutrition, milk formulation and iron fortification.
DMT1-mediated Fe2+ transport is energized by the H+ electrochemical gradient, placing DMT1 in a large and important class of membrane proteins we call cotransporters. Mammalian cotransporters use Na+ or H+ electrochemical gradients as the energy source to drive uphill (concentrative) transport of a broad range of nutrients or solutes. I am also studying the Na+-coupled amino acid transporters of the System A family and their roles in neurotransmission, and the Na+-coupled ascorbic acid (vitamin C) transporter SVCT1. The approaches I am using include the voltage clamp, radiotracer assays and fluorescence-based assays in RNA-injected Xenopus oocytes, together with the use of genetically-modified animal models.