L02 – Iron Metabolism and Heme Biosynthesis Flashcards
Why is iron used for oxygen transport?
abundant metal with multiple oxidation states
useful as a relay for transferring electrons from one molecule to another
What are the oxidation states in which iron exist in the body? (intra and extracellular)
Intracellular: Fe2+, bound to ferritin
Extracellular = Fe3+, diferric transferrin mainly, minority with albumin and low molecular weight compound
How is iron incorporated into the RBC life cycle? How is it recycled?
Erthyroid cells (ie reticulocyte) take up Fe for heme synthesis
> > erythroid cells mature
> > RBC life cycle ends
> > mononuclear phagocytes in spleen, bone marrow and liver degrade senescent RBC
> > Release Fe to blood again
Iron can be excreted by feces. True or False.
False
No mechanism for excreting Fe, Fe can only be lost uncontrollably
List ways to lose iron from body?
Sweating
Blood loss, menses
Exfoliation of epithelial cells from body
Sequence of the Fe homeostasis cycle?
Loss of Fe uncontrollably
> > Depletion of total Fe pool (i.e. by blood lost or growth/ development causing increased demand)
> > Stimulate dietary uptake of Fe (uptake is controllable)
> > Repletion of total Fe pool
Major and minor modes of Fe transport in blood? (include the mechanisms)
- Major- high affinity:
Apotransferrin + Fe3+ = monoferic transferrin + Fe3+ = Diferric transferrin - Minor - low affinity Non-transferrin bound iron (NTBI):
- Serum albumin + Fe3+ = iron-bound serum albumin
- Low molecular weight compounds (non- protein)
3 mechanisms to prevent iron overload in blood?
- Large buffer/reserve of free Transferritin – high affinity for Fe
- Non-protein compounds provide further Fe-binding capacity
- Cells take up excess Fe in blood
> > > Very low concentration of free Fe in plasma
Hb structure consists of?
- Globin polypeptides (α chain, β chain)
- Porphyrin structure
- Iron (Fe)
Structure of heme?
Fe forms complex with porphyrin:
- Chelating design holds Fe in centre
- Orbitals of Fe partially engaged
> > restricts/stabilizes reactivity of Fe2+ and prevents Fe from reacting with O2
Explain why free heme is toxic?
Free heme turns organic hydroperoxides, unsaturated fatty acids, alcoholic compounds into free radicals, superoxide anion
> > oxidative damage and chemical alterations
How is the toxicity of free heme reduced?
Interacts with the amino acid residues of globin chains
Formation of heme intracellularly?
ALAS turns Glycine + succinyl CoA (from TCA cycle) into ALA at inner mitochondrial membrane
Exported to cytosol for intermediate reactions to form Coproporphyrinogen III
Uptake back into mitochondria and reaction with CPO, PPO, FC enzymes in the intermembrane space
> > form heme at matrix of mitochondria
Function of ALAS in heme synthesis?
ALA synthase:
Enzyme for the first step of condensing Glycine with Succinyl CoA to make ALA
What endogenous compound stimulates ALA transcription?
Erythropoietin (EPO): made by kidney, liver
> > activate Erythroblast-specific transcription factors
> > Stimulate ALAS- 2 gene transcription to ALAS- 2 mRNA
What triggers the translation of ALAS-2 mRNA? (IRE mechanism?)
Iron-responsive-Element (IRE) is present in the 5’untranslated region of the ALAS-2 mRNA
No Fe: Iron regulatory protein (IRP) binds to stem loop structure of IRE, block translation of ALAS-2
Fe present: Fe-S cluster forms in IRP, change conformation and dissociate IRP from IRE. Allow translation of ALAS-2
What inhibits the translation of ALAS-2 mRNA apart from IRE?
HRI
Heme regulatory inhibitory protein
blocks the binding of initiator tRNA to small ribosomal subunit to start ALAS-2 translation
Mechanism of HRI in control of ALAS-2 translation?
Heme blocks action of HRI by inactivating its protein kinase
> > HRI cannot phosphorylate small ribosome subunit, allow initiator tRNA to bind
> > ALAS-2 translation into ALAS-2 protein = makes more ALA = makes more heme in presence of Fe
> > more heme removes HRI inhibition
> > positive feedback to make more heme
How is the ALAS-2 translation regulated?
1) ALAS-2 translation permitted by Fe binding to IRP, removing inhibition on IRE
2) HRI mechanism
3) ALAS- 2 translation into ALA makes more heme ONLY IN THE PRESENCE OF FE
» excess heme block Fe import by inhibiting formation of Transferrin/Fe3 + transferrin receptor complex
Describe the import of Fe from blood into cell?
Transferrin-bound Fe3+ binds to transferrin receptor
> > endocytosis into erythroid cell (reticulocytes)
Describe the reactions that occur after endocytosis of Tf-Fe3+ complex from blood into cell?
Turn Transferrin- Fe3+ into Fe2+ inside the endosome:
Tf-Fe3+»_space; enzyme ferrireductase steap3**»_space; apotransferrin + Fe2+
- Fe2+ exit endosome by DMT1**
- Apotransferrin and Transferrin receptors are recycled to cell surface
Summarize how Heme can terminate Hb synthesis?
Fe uptake into cell increases heme synthesis
> > Increased [Heme] blocks import of Fe via Transferrin- Fe3+ endocytosis
> > Decrease [Fe] intracellularly
> > Less Fe2+ able to complete ALAS-2 translation
> > Less ALAS-2 protein to form ALA
> > Decrease heme synthesis, thus terminate Hb synthesis
Which Hb constituents are toxic?
All are toxic
Fe in excess of the other two components: toxicity, oxidative stress
Porphyrin in excess: toxicity (Related hereditary disorders known as porphyria)
Globin in excess: also toxic by causing protein stress in cells
How is Fe pool in body maintained without dietary input or uncontrolled loss?
Degradation of senescent red cells can recycle Fe
