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Metal ion metabolism

Metal ion metabolism. In order for metal ions to fulfill their physiological functions there must be regulatory systems to ensure that: Metal ions are acquired by the organism Metal ions are delivered to the cells that require them

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Metal ion metabolism

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  1. Metal ion metabolism • In order for metal ions to fulfill their physiological functions there must be regulatory systems to ensure that: • Metal ions are acquired by the organism • Metal ions are delivered to the cells that require them • Metal ions are processed, conserved and recycled by those cells • Unnecessary or excess metal ions are eliminated

  2. Classes of Iron-containing Proteins Functional proteins heme proteins (oxygen carriers, oxygen activators, electron transfer) iron-sulfur proteins (electron transport – ferridoxins, rubredoxins) (enzymes – nitrogenase, aconitase) non-heme, non-iron-sulfur proteins (dioxygenases, monooxygenases, superoxide dismutase) Transport and Storage proteins ferritin hemosiderin transferrin Regulatory Proteins iron regulatory proteins (IRPs) ferroportin hepcidin ceruloplasmin

  3. Functional iron proteins heme proteins non-heme, non-Fe/S proteins

  4. Iron compounds in humans Iron is an absolutely essential element for life Organisms will take extraordinary measures to ensure that they have sufficient levels of iron Where is most of this iron found in humans? classes of adult human Fe compound (mg) The average adult body contains 3.8 g of iron More than half of the iron is found in hemoglobin, which functions in the transport of oxygen

  5. Iron uptake in bacteria Different species use different approaches to obtain sufficient iron to ensure their survival These high affinity iron transport systems use a number of membrane bound proteins to move these iron complexes into the cell several hydroxamate-type siderophores are used to sequester iron in E. coli Some of these siderophores are produced by other microbial species The energy for iron uptake is provided by coupling to energy driven proteins located in the inner membrane Once inside the cell the reduced iron is distributed to different iron-requiring proteins

  6. Iron uptake in plants Iron acquisition is more complicated in plants, with both adaptive and non-adaptive mechanisms

  7. Iron uptake in mammals There are several routes by which iron is taken into mammalian cells One involves binding and transport by transferrin after binding to a receptor the Fe-transferrin complex is encapsulated the iron-free transferrin is exported from the cell to bind additional iron the Fe-transferrin vesicles are taken into cells and then uncoated the released iron can be stored in ferritin or transferred to other proteins an ATP driven proton pump lowers the pH in the endosome to allow release of the Fe

  8. Iron transferrin Lactoferrin, an iron-transferrin, contains a large cavity Iron binds in this cavity along with a carbonate anion and induced a conformational closing of the domains This closing is induced by new bonds formed between the bound Fe-carbonate and protein functional groups in each domain

  9. Iron Uptake in mammals Alternatively, free Fe2+ can be bound by a channel protein (DCT1) Binding of protons moves the iron through the channel and releases the iron to the interior of the cells B.B.A.1763, 609 (2006)

  10. Regulation of iron uptake Iron regulatory proteins (IRPs) are the key iron sensors in mammalian cells When iron levels are low IRPs repress the translation of Fe-requiring proteins and stabilize the transferrin mRNA During periods of high iron levels IRPs lose their affinity for binding to mRNA regulatory elements IRP1 gains a 4Fe/4S cluster and acquires an aconitase activity IRPs can no longer stabilize transferrin mRNA, leading to decreased protein synthesis and lower iron uptake B.B.A.1763, 668 (2006)

  11. Regulation of iron uptake IRP2 has a low affinity for mRNA binding sites unless phosphorylated At higher iron levels Fe or Fe-heme binding leads to recognition by a ligase that ubiquinates IRP2 for degradation B.B.A.1763, 668 (2006) Fe-chelators stabilize IRP2 against degradation The activity of IRPs are enhanced by low Fe and low O2 and also by high NO and peroxide levels IRPs are inactivated by high Fe, leading to Fe-S cluster addition (IRP1) and degradation (IRP2) Cell117, 285 (2004)

  12. Iron exchange in mammals Once adsorbed iron is distributed to many different cell types and tissues, with dramatically different iron levels and rates of exchange

  13. Iron distribution There is a cycle for the trafficking of iron between different cell types, with the Fe levels in each cell population shown Daily turnover is about 20-25 mg/day The liver and other tissues also contain significant iron levels Daily loses and re-adsoprtion levels are quite low Cell117, 285 (2004)

  14. Iron Transport Different cells and tissues have different functions and play different roles in iron transport Transferrin is the transporter that moves iron to different cells Intestinal cells White blood cell Iron import Release of iron from destruction of pathogens Transfer to the blood for distribution Uptake of iron by cells Release of intracellular iron B.B.A.1763, 609 (2006)

  15. Iron metabolism Iron uptake occurs either as Fe-transferrin or free Fe3+, with subsequent conversion to intracellular Fe2+ Fates of Intracellular Iron I. utilization and storage II. transport to mitochondria for cofactor production III. export of Fe2+ facilitated through oxidation by hephaestin (HP) or ceruloplasmin (CP) B.B.A.1763, 668 (2006)

  16. Iron metabolism direct import of Fe2+ cytochrome b ferric reductase iron uptake heme scavenger synthesis of iron cofactors Fe3+ reduction acidic for Fe release transferrin recycling Fe2+ oxidation iron export Cell117, 285 (2004)

  17. Iron storageferritin each subunit is composed of 5 helices and a long interhelix strand (L) 24 identical subunits assemble into a capsule that encloses an interior cavity in which iron is stored iron uptake and release is controlled through channels that are present between the subunits As Fe2+ is imported it is oxidized to Fe3+ When needed iron is released from the microcrystalline surface, with the last iron added released first The iron is stored as a crystalline lattice built up of Fe3+-peroxide complexes

  18. Summary • Iron is essential for all living organisms • There are specific proteins to acquire, transport and store iron, and also to regulate the distribution of iron • Functional protein targets for iron includes heme proteins, Fe/S proteins, and non-heme, non-Fe/S proteins • Iron uptake is a highly specialized process that is handled differently in microbes, plants and mammals • In mammals uptake involves transferrin as a carrier or alternatively the direct uptake of free Fe2+ • Regulatory proteins control the expression of functional iron proteins and transferrin • Different mammalian cells and tissues have different roles in iron metabolism

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