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Bryan Mackenzie, PhD
Associate Professor

Iron deficiency is the most prevalent micronutrient deficiency worldwide. Meanwhile iron overload associated with conditions like hereditary hemochromatosis or thalassemia 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 iron 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. Export of iron from enterocytes and from macrophages (recycling iron from senescent red blood cells) is thought to be mediated by ferroportin (Fpn). Whereas Fpn was identified a decade ago, very little is known about how this transporter works.

We are investigating the molecular mechanisms, substrate selectivity and structure–function relationships of DMT1 and Fpn. Our work has revealed that both DMT1 and Fpn are iron-preferring transporters that are reactive also with certain other transition metals. DMT1 is essential for the intestinal absorption of iron but is not required for the absorption of copper, manganese or zinc. We established that DMT1-mediated Fe2+ transport in vitro is H+-coupled but the provenance of the H+ electrochemical potential gradient in vivo was not known. We have identified a role for the Na+/H+ exchanger-3 (NHE3) in generating the proton-motive force driving iron uptake via DMT1 and thereby energizing iron absorption.

The approaches we use include the voltage clamp, radiotracer assays, and fluorescence-based assays in RNA-injected Xenopus oocytes, together with the use of genetically-modified animal models (including the intestine-specific DMT1 knockout mouse, and intestinal Na+/H+ exchanger nulls).

Selected Publications:
  • Ali Shawki, Melinda A Engevik, Robert Kim, Patrick B Knight, Rusty Baik, Sarah A Anthony, Roger T Worrell, Gary E Shull, and Bryan Mackenzie (2016) Intestinal brush-border Na+/H+ exchanger-3 drives H+-coupled iron absorption in the mouse. Am J Physiol Gastrointest Liver Physiol 311, in press.
  • Ali Shawki, Sarah R Anthony, Yasuhiro Nose, Melinda A Engevik, Eric J Niespodzany, Tomasa Barrientos, Helena Öhrvik, Roger T Worrell, Dennis J Thiele, and Bryan Mackenzie (2015) Intestinal DMT1 is critical for iron absorption in the mouse but is not required for the absorption of copper or manganese.Am J Physiol Gastrointest Liver Physiol 309, G635–G647.
    View original publication at AJP:GI Online
  • Colin J Mitchell, Ali Shawki, Tomas Ganz, Elizabeta Nemeth, and Bryan Mackenzie (2014) Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc. Am J Physiol Cell Physiol 306, C450–C459.
    View original publication at AJP:Cell Online
  • Ali Shawki, Patrick B Knight, Bryan D Maliken, Eric J Niespodzany, and Bryan Mackenzie (2012) H+-coupled divalent metal-ion transporter-1: Functional properties, physiological roles and therapeutics. Curr Top Membr 70, 169–214. [Review]
    View original publication at ScienceDirect.com
  • Anthony C Illing, Ali Shawki, Christopher L Cunningham, and Bryan Mackenzie (2012) Substrate profile and metal-ion selectivity of human divalent metal-ion transporter-1. J Biol Chem 287, 30485–30496.
    View original publication at JBC.org
Publications, Complete List at PubMed

Publications and Citations at Google Scholar

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