Iron plays an integral role in many biochemical processes essential to life. For example, iron containing metalloproteins are necessary for the synthesis of DNA, respiration and many key metabolic reactions. Thus, life as we know it is fully dependent on iron. However, the same properties that allow iron to play a central role in the chemistry of life, also lead to potentially deleterious effects. Specifically, excess Fe2+ combines with naturally occurring peroxide to produce the hydroxyl radical, one of several reactive oxygen species (ROS) that contribute to oxidative stress, reacting indiscriminately with DNA, proteins and lipids. Hence, iron levels must be carefully balanced so that enough iron is present to sustain key metabolic processes, but production of ROS are minimized. To this end, an elaborate system of transport, storage and regulatory proteins has evolved to effect iron homeostasis in humans and other organisms, including human pathogens. 

Importantly, disorders of iron metabolism are among the most prevalent diseases in humans. For example, iron deficiency is thought to affect more than one billion people worldwide, and is, particularly problematic in pregnant women and young children. In addition, the anemia of inflammation, a down regulation of iron levels in response to inflammation, is the most common form of anemia in hospitalized patients, and in patients with chronic diseases such as heart failure, rheumatoid arthritis, renal disease, and cancer. Similarly, inherited iron overload disorders, collectively known as hereditary hemochromatosis, are also common. For example, the occurrence of a single disease associated allele, HFEC282Y, is as high as 10% in individuals of Northern European descent, and is the most common autosomal recessive disease currently known. In homozygous individuals, progressive iron accumulation generates oxidative stress that results in significant cellular damage, inducing inflammation and fibrosis that eventuates in hepatic cirrhosis, hepatocellular carcinoma, diabetes mellitus, cardiac insufficiency and arthropathy. In addition, excess iron and/or oxidative stress is a factor in many neurodegenerative diseases, including Parkinson’s, Huntington’s, Alzheimer’s and ALS. 

Consequently, the cellular machinery responsible for iron transport and homeostasis is worthy of significant investigation, and may provide potential targets for pharmacological intervention, to either promote or inhibit systemic or cellular iron uptake, or to interfere with iron acquisition in human pathogens, where iron availability is frequently the rate limiting nutrient. In this light, we are engaged in structural studies of both human and bacterial proteins involved in iron transport and homeostasis. 


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Structure, Biochemistry