Uptake and storage of iron Flashcards
Why does iron have a low bioavailability, despite its high abundance in the Earth’s crust?
The predominant state of iron in aqueous, non-acidic, oxygenated environments is Fe3+
An oxidising atmosphere produces Fe(OH)3 which is insoluble
What is the growth-limiting factor in the oceans?
The availability of iron
What are the 3 ways metal (complexes) can pass through cell membranes?
- Passive diffusion of neutral complexes e.g. cis-platin
- Migration through ion channels (cationic/anionic)
- Specific receptor proteins complex to a specific ion and pass the metal into the cell –> this is used for Fe uptake
What properties must a receptor protein that passes iron into cells have?
Form water-soluble Fe(III) complexes
High complexation constant
Easily produced for release into the environment
What do microorganisms use for iron uptake?
Siderophores
Fe/siderophore complexes are recognised by receptors on the microorganism surface and reabsorbed
(Fe(III) then reduced to Fe(II) inside the microorganism, which is less tightly held and becomes available for use)
Siderophores
Amongst the strongest Fe3+ binders know Solubilise Fe(III)
Enterobactin
High affinity siderophore (K = 10^49 M^-1)
Highly selective for iron over other metals
Primarily found in Gram-negative bacteria e.g. E. coli
Enterobactin amide groups
Responsible for recognition by the receptor
Enterobactin catechol groups
Required for Fe chelation, not membrane recognition
How is the biosynthesis of enterobactin controlled?
By Ferric Uptake Regulator (FUR) protein at the transcriptional level
How is the biosynthesis of enterobactin/siderophores controlled?
By Ferric Uptake Regulator (FUR) protein at the transcriptional level
Excess Fe(II) binds to FUR protein
The resulting complex binds to DNA, blocking transcription of the siderophore gene
Hemosiderin
Even larger iron storage complex for Fe overload
Complex of ferritin, denatured ferritin and other material
Can store >20000 Fe atoms (35 % wt. Fe)
Insoluble - only intracellular, doesn’t circulate
Iron within hemosiderin is poorly bioavailable
Structure of ferritin
Protein shell - 10 Å thick, 100 Å diameter
Fe bound by Asp, Glu and Tyr residues
Most of the Fe in an Fe2O3 core that may contain various anions e.g. hydroxide, phosphate
Apoferritin
Iron-free ferritin
Filled with water molecules
Hydrophilic and hydrophobic channels
Uptake of Fe by ferritin
Fe is introduced as Fe(II) then oxidised by O2 inside ferritin
12Fe2+ + 3O2 + 12H2O 6Fe2O3 + 24H+
> 10000 H+ released during filling of one ferritin protein
H+ must diffuse slowly in and out of ferritin (subtle pH control)
Therefore oxidation of Fe(II) is slow
Iron transport proteins
Transferrin
Lactoferrin
= iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids
Keep iron soluble, allow it to be transferred across cell membranes
Transferrin
80 kDa, 6 % sugar
Two high affinity Fe(III)-binding sites
Binds iron tightly but reversibly
Bound by Asp, Tyr and His residues as well as a carbonate anion (anion required for Fe to bind)
Mechanism of release of Fe from transferrin
When a transferrin protein loaded with iron encounters a transferrin receptor on a cell surface, it is transported into the cell by receptor-mediated endocytosis
The vesicle interior is acidified to pH 5.5, leading to displacement of Fe from the carbonate by H+ (H+ is a better Lewis acid)
Regulation of ferritin and transferrin biosynthesis
Controlled at the translation stage by [Fe]
Low [Fe] = slow translation of ferritin, fast translation of transferrin
High [Fe] = fast translation of ferritin, slow translation of transferrin
IRE
Iron Response Element
Bound by Iron Response Proteins (IRPs)
Located in the UTRs of the mRNA of proteins involved in iron metabolism
IREs in regulation of ferritin and transferrin biosynthesis
IRE at 5’ UTR of ferritin mRNA
At low [Fe], IRPs bind to the IRE leading to a reduced rate of translation
IRE at 3’ UTR of transferrin mRNA
At low [Fe], IRP binding to IREs increases the stability of the mRNA, so translation continues
How is the affinity of IRPs for IREs regulated?
By [Fe]
At low [Fe], K = 10^11 M^-1 (i.e. high affinity)
So less ferritin, more transferrin
At high [Fe], K = 5 x 10^9 M^-1 (i.e. lower affinitY)
So more ferritin, less transferrin
What are the 5 processes involved in iron homeostasis?
- Uptake - active or passive during food ingestion
- Transport - selective movement of Fe ions through membranes into particular cells
- Utilisation - in cellular processes e.g. incorporation into a protein
- Storage - of excess iron in a non-toxic, easily accessible form
- Elimination - controlled removal of iron from the system by excretion
Iron deficiency
Can lead to anaemia, which can cause acute health problems
Iron excess
= haemochromatosis
Excess iron can deposit in tissues and cause radical damage
Implicated in coronary disease
Treatment for iron poisoning
Chelation therapy to remove excess iron via the kidneys
Desferrioxamine = ligand of choice
(enterobactin too easily hydrolysed)
How do pathogenic microorganisms scavenge a supply of iron from the host?
Absord iron directly from the blood plasma, leading to a decrease in blood iron levels
Treated with iron-scavenging ligands e.g. desferrioxamine (so no free iron available to pathogen)
Where do animals absorb iron from?
The gut
