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Metal Ion Transport and Storage

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J. A. Cowan Inorganic Biochemistry: An Introduction VCH Publishers, 1994. ... O2 transport (hemocyanin in crustacean and mollusks) O2 activation (Cu oxidases) ... – PowerPoint PPT presentation

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Title: Metal Ion Transport and Storage


1
Metal Ion Transport and Storage
  • Tim Hubin
  • March 3, 1998

2
References
  • J. J. R. Frausto da Silva and R. J. P. Williams
    The Biological Chemistry of the Elements,
    Clarendon Press, Oxford, 1991.
  • J. A. Cowan Inorganic Biochemistry An
    Introduction VCH Publishers, 1994.
  • S. J. Lippard and J. M. Berg Principles of
    Bioinorganic Chemistry, University Science Books,
    1994.
  • M. D. Yudkin and R. E. Offord A Guidebook to
    Biochemistry, Cambridge University Press, 1980.
  • CHM 986, Spring 1997, Prof. Grover Everett,
    University of Kansas.

3
Outline
  • General Concepts
  • Abundance of Metal Ions in Biology
  • Challenges in Transport and Storage of Metal Ions
  • Membrane Transport
  • Specific Metal Ions
  • Sodium and Potassium
  • Calcium
  • Iron
  • Copper
  • Zinc

4
Need for Metal Ions
  • Metal ions must be obtained for growth and
    development

5
General Transport/Storage Problems
  • Capture of Trace Ions from the Environment
  • Homeostatic Control of Concentration is essential
    for life
  • Bulk ions present in high concentration
  • Trace ions must be actively accumulated
  • Trace ions are often insoluble
  • Selectivity of Ion Uptake is Essential
  • Toxic ions must be excluded
  • Beneficial ions must be accumulated
  • Specialized Moleculecules have evolved

6
General Transport/Storage Problems
  • Charged Ions must pass through a Hydrophobic
    Membrane
  • Neutral gases (O2, CO2) and low charge density
    ions (anions) can move directly through the
    membrane
  • High charge density cations require help
  • Once inside the cell, metal ions must be
    transported to the location of their use, then
    released or stored for later
  • Release from ligand is often not trivial
  • Storage requires additional molecules

7
Mechanisms for Membrane Transport
  • Ionophores special carrier molecules that wrap
    around metal ions so they can pass through the
    membrane by diffusion
  • Ion Channels large, membrane-spanning molecule
    that form a hydrophilic path for diffusion
  • Ion Pumps molecules using energy to transport
    ions in one direction through a membrane

8
Mechanisms for Membrane Transport
  • Passive Transport moves ions down the
    concentration gradient, requiring no energy
    source
  • Ionophores and Ion Channels are Passive
  • Active Transport moves ions against the
    concentration gradient, requiring energy from ATP
    hydrolysis
  • Ion Pumps are Active
  • Choice of Transport Mechanism
  • Charge
  • Size
  • Ligand Preference

9
Sodium and Potassium
  • Function
  • Simple Electrolytes to create potentials (along
    with Cl-)
  • Provide counter ions for DNA, membranes, etc...
  • Nerve action
  • Concentrations Na outside cells, K inside
    cells
  • Inside Red Blood cells Na 0.01 M K
    0.09 M
  • Outside (Blood Plasma) Na 0.16 M K
    0.01 M
  • Ion Pump is required to maintain concentration
    gradients

10
Sodium and Potassium--Ion Pump
  • Na/K-ATPase
  • Membrane-Spanning Protein Ion Pump
  • a2b2 tetrameric 294,000 dalton protein
  • Conformational changes pump the ions one
    conformation binds Na best, the other binds K
    best
  • Hydrolysis of ATP provides the energy for
    conformational changes (30 of a mammals ATP is
    used in this reaction)
  • Antiport transport like charged ions are
    transported in opposite directions
  • Reversing the normal reaction can generate ATP
  • Reaction can occur 100 time per second

3Nain 2Kout ATP4- H2O
3Naout 2Kin ADP3- HPO42- H
11
Sodium and Potassium--Ionophore
  • Nonactin microbial Na and K ionophore
  • Makes Na and K membrane soluble when complexed
  • Oxygen Donors can be modeled by Crown Ethers

Nonactin
12
Sodium and Potassium--Ion Channel
  • Gramicidin ion channel-forming molecule
  • Helical peptide dimer
  • Hydrophobic outer surface interacts with membrane
  • Carbonyls and Nitrogens on inner surface can
    interact with cations as they pass through
  • Potassium selective pore size and ligands select
    for K
  • Channels can be Voltage-Gated or activated by the
    binding of a Chemical Effector which changes the
    conformation
  • 107-108 ion/second may pass (Emem 100 mV)

13
Calcium
  • Function
  • Signal pathways (Ex Muscle Contraction)
  • Skeletal Material
  • Concentration
  • Outside of Cell Ca2 0.001 M
  • Inside Cell Ca2 10-7 M
  • Ca2-ATPase in Cell Membrane controls
    concentration

14
Calcium--Muscle Contraction
  • Muscle Cells
  • Sarcoplasmic Reticulum(SR) muscle cell organelle
  • Ca2-ATPase pumps Ca2 into SR to concentrations
    up to 0.03 M
  • Inside SR, Ca2 is bound by Calsequestrin, a
    40,000 dalton protein (50 Ca2 per molecule)
  • Hormone induced stimulation of ion channels
    releases Ca2 from the SR into the muscle cell
    causing contraction

15
Calcium--Storage
  • CaCO3 in a protein matrix makes up egg shells and
    coral skeletons
  • Calcium Hydroxyapatite in a collagen framework is
    the stored form of Ca2 in bones and teeth
    Ca10(PO4)6(OH)2
  • Collagen triple helix fibrous protein
  • Hydroxyapatite crystallizes around the collagen
  • Replacement of OH- by F- prevents tooth decay
    because F- is a weaker base
  • When needed, Ca2 can be released and reabsorbed

16
Iron
  • Iron is the most abundant transition metal ion in
    biological systems--almost all organisms use it
  • Availability
  • Most abundant transition metal on the Earths
    crust
  • Nuclear Binding Energy is maximized at 56Fe
  • Versatility
  • Fe2/Fe3
  • High Spin/Low Spin
  • Hard/Soft
  • Labile/Inert
  • Coordination Number 4,5,6

17
Iron--Evolution
  • When life began
  • Reducing Atmosphere H2, H2S, CH4, NH3---gt Fe2
    used
  • Ksp(Fe(OH)2) 4.9 x 10-17 Fe2 5.0 x 10-3
  • After Photosynthesis
  • Oxidizing Atmosphere O2---gt Fe3 used
  • Ksp(Fe(OH)3) 2.6 x 10-39 Fe3 2.6 x
    10-18
  • Specialized Molecules were developed to
    solubilize Fe3 and protect Fe2 from oxidation
  • FunctionsO2 transport, electron transfer,
    metabolism

18
Iron--Siderphores
  • Siderophores class of bacterial ionophores
    specific to Fe3
  • Small molecules released into the environment
  • Complexation of Fe3 solubilizes it for uptake
  • Ligands are Catechol and Hydroxamic Acid chelates
  • Enterobactins 3 catechols
  • Ferrichromes 3 hydroxamic acids, cyclic peptide
  • Ferrioxamines 3 hydroxamic acids, acyclic peptide

Catechol
Hydroxamic Acid
19
Iron-Enterobactin
  • Structure 3 catechol chelates bound to a
    12-membered ring
  • Kf Fe(ent)3-/Fe3ent6- 1049
  • Complex anion is soluble
  • Spectroscopy
  • UV-Vis like Fe(cat)33-
  • D structure assigned by Cr(ent)3-
  • circular dichroism
  • Crystal Structure V(ent)2-

20
Iron-Enterobactin
  • Getting Fe3 into the cell
  • Fe(ent)3- binds to an uncharacterized receptor
    on cell surface
  • Active transport process takes the complex inside
  • Mechanism of iron release is still unknown
  • Hydrolysis of ligand
  • Reduction to Fe2 would labilize ion
  • Ered -750 mV vs NHE at pH 7
  • Lowering pH would facilitate reduction
  • Intracellular ligand

21
Iron-Transferrin
  • Transferrin Mammalian transport ab dimer protein
  • 80,000 dalton protein carries 2 Fe3 ions in
    serum
  • Iron captured as Fe2 and oxidized to Fe3
  • CO32- must bind at same time Synergism
  • Taking Iron into the cell--Endocytosis

22
Iron--Ferritin
  • Family of protein found in animals, plants, and
    bacteria
  • Structure
  • symmetric, spherical protein coat of 24 subunits
  • Subunits are 175 amino acids, 18,500 daltons each
  • Channels on 3-fold axes are hydrophilic iron
    entry
  • Inside surface is also hydrophilic
  • Inner cavity
  • 75 Å inner diameter holds 4500 iron atoms
  • Iron stored as Ferrihydrate Phosphate
    (Fe(O)OH)8(FeOPO3H2) . nH2PO4
  • Iron-protein interface binding of core to
    protein is believed to be through oxy- or
    hydroxy- bridges

23
Iron-Ferritin
  • Iron thought to enter as soluble Fe2, then
    undergo oxidation by O2 in channels or inside the
    cavity
  • Biomineralization synthesis of minerals by
    organisms
  • Ferritin is synthesized as needed
  • Normal iron load is 3-5 grams in a human
  • Ferritin is stored in cells in the bone marrow,
    liver, and spleen
  • Siderosis iron overload (60 g can be
    accumulated)
  • doposits in liver, kidneys, and heart
  • treated by Chelation Therapy (desferrioxamine)

24
Copper
  • Function
  • O2 transport (hemocyanin in crustacean and
    mollusks)
  • O2 activation (Cu oxidases)
  • electron transfer (plastocyanin)
  • Availability
  • Third most abundant transition metal ion in
    organisms
  • 300 mg in a human body
  • Ksp(Cu(OH)2) 2.6 x 10-19 Cu2 2.6 x 10-5
  • Solubility means less specialized transport and
    storage

25
Copper--Transport
  • Ceruloplasmin
  • 132,000 dalton glycoprotien (7 carbohydrate)
  • Binds 95 of the Cu2 in human plasma
  • 6 Cu2 sites 1 Type I, 1 Type II, 4 Type III

26
Copper--Transport
  • Ceruloplasmin
  • Biological role not fully understood
  • transport
  • oxygen metabolism
  • Wilsons Disease
  • genetic disorder of low ceruloplasmin levels
  • Cu2 accumulates in the brain and liver
  • treated by chelation therapy (EDTA)

27
Copper--Storage
  • Metallothioneins
  • Small (6000 dalton) metal storage protein family
  • 20 cysteine residues select for soft metals
  • Cu, Zn2, Cd2, Hg2, Pb2
  • X-Ray structure of Cd2/Zn2 complex shows
    tetrahedrally coordinated metal clusters
  • Up to 20 Cu can bind
  • Mechanism of Cu and Zn2 homeostasis
  • Detoxification by removal of soft ions Cd2,
    Hg2, Pb2

28
Zinc
  • Function
  • Lewis Acid catalyst
  • Structural control
  • Substrate binding
  • 200 Zn2 proteins known
  • Availability
  • abundant in biosphere, highly soluble
  • all forms of life require it (2 g in a human)
  • Versatile labile, varied geometries (no LFSE),
    hard/soft
  • No redox chemistry

29
Zinc
  • Transport Serum Albumin
  • Constitutes more than half of all serum protein
  • plays a role in Cu2 transport as well
  • 600 amino acid protein
  • poorly described
  • Zn2 pumps?
  • high concentrations in some vesicles suggest
    pumps
  • Zn2cytoplasm 10-9 M Zn2vesicle 10-3
    M
  • Storage Metallothionein chemistry similar to
    Cu2

30
Summary
  • Transport and Storage of Metal ions
  • Necessary
  • Diverse
  • Evolved
  • Largely Unknown
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