Lecturio - Heme Synthesis, Iron Transport and Storage Flashcards
Structure of heme
Heme is a flat, planar structure containing a porphyrin ring with an atom of Fe2+ at the center.
Hemes usually found attached to ____
proteins
(Heme is a flat, planar structure containing a porphyrin ring with an atom of Fe2+ at the center.)
Examples of hemes?
Examples hemoglobin, myoglobin, cytochromes
(Heme is a flat, planar structure containing a porphyrin ring with an atom of Fe2+ at the center.)
Describe heme in cholorphyll
Related ring found in chlorophyll with Mg at center
What can we have instead of Fe?
Cobalamins (B12) have cobalt at center.
What are the 4 types of hemes
What are the 4 types of hemes
Function of Heme A?
Part of complex IV of electron transport system
Function of Heme B?
- Most common type
- In hemoglobin, myoglobin, peroxidase and cycloxygenase
- Other proteins include P450 and nitric oxide synthase
Function of Heme C?
Found in cytochrome C proteins links to protein via cysteines
Function of Heme O?
Functions in bacterial oxygen reduction, like heme A
Identify
Identify
How many steps does heme synthesis consist of?
7 steps
Heme Synthesis First Step
-> Synthesis begins with ___ and ___
succinyl-CoA and glycine.
Heme Synthesis - First Step
-> Identify the molecules and enzyme
1/ Glycine
2/ Succinyl-CoA
3/ Aminolevulinic acid
A - Aminolevulinic (ALA) synthetase
Heme Synthesis - First Step
-> Identify
1/ CO2
2/ CoAsh
Heme Synthesis - First Step
-> Is Aminolevulinic acid (ALA) synthase a cytosol or mitochondrial enzyme?
Mitochondrial enzyme (near succinyl-CoA)
Heme Synthesis - First Step
-> Synthesis tightly controlled by presence of ____
Fe2+ binding proteins
What happen in second step of heme synthesis?
Condensation of two aminolevulinic acids yields porphobilinogen.
Heme Synthesis - Second Step
-> Identify these molecule(s) and enzyme
Heme Synthesis - Second Step
-> Porphobilinogen synthase sensitive to ___ and _____
Mg2+ and pH
Heme Synthesis - Second Step
-> Porphobilinogen synthase is aso very easily inactivated by ____
heavy metal
What happen in the 3rd step of heme synthesis?
Four porphobilinogens combine with splitting out of ammonia to form hydroxymethylbilane.
Heme Synthesis - 3rd step
-> Identify molecule(s)/ enzyme(s)
1/ Porphobilinogen
2/ Hydroxymethylbilane
3/ Porphobilinogen deaminase
Heme Synthesis - 3rd step
-> Molecules are joined through their ___
amine rings.
Heme Synthesis - 3rd step
-> Reduced activity of enzyme results in ____
intermittent porphyria.
What happen in Heme Synthesis - Fourth Step?
Uroporphyrinogen III is the first cyclic intermediate of the pathway.
Heme Synthesis - Fourth Step
-> Identify molecule(s)/ enzyme(s)
1/ Hydroxymethylbilane
2/ Uroporphyrinogen III
3/ Uroporphyrinogen III synthase
Heme Synthesis - Fourth Step
-> Hydroxymethylbilane can also spontaneously cyclize to ____ (except Uroporphyrinogen III)
uroporphyrinogen I.
Heme Synthesis - Fourth Step
-> Uroporphyrinogen III synthase deficiency associated with ____
congenital erythropoietic porphyria
What happen in Heme Synthesis - Fifth Step?
Decarboxylation of uroporphyrinogen III yields coproporphyrinogen III.
Heme Synthesis - Fifth Step
-> Identify molecule(s)/ enzyme(s)
1/ Uroporphyrinogen III
2/ Coproporphyrinogen III
Heme Synthesis - Fifth Step
-> Mutations in Uroporphyrinogen III decarboxylase cause ___ and _____
familial porphyria cutanea tarda and hepatoerythropoietic porphyria
What happen in Heme Synthesis - Sixth Step?
In this reaction, coproporphyrinogen III is converted to protoporphyrinogen IX through two sequential steps of oxidative decarboxylation.
Heme Synthesis - Sixth Step
-> Identify molecule(s)/ enzyme(s)
1/ Coproporphyrinogen III
2/ Protoporphyrinogen IX
A - Coproporphyrinogen III oxidase
Heme Synthesis - Sixth Step
-> Reduced amounts of coproporphyrinogen III oxidase leads to ___
hereditary coproporphyria.
Heme Synthesis - Sixth Step
-> characteristics of coproporphyrinogen III oxidase
- Coproporphyrinogen III oxidase is a mitochondrial, iron-carrying enzyme.
What happen during Heme Synthesis - Seventh Step?
In this reaction, protoporphyrin IX is formed from protoporphyrinogen IX by oxidation.
Heme Synthesis - Seventh Step
-> Identify molecule(s)/ enzyme(s)
1/ Protoporphyrinogen IX
2/ Protoporphyrin IX
A - Protoporphyrinogen oxidase
Heme Synthesis - Seventh Step
-> Protoporphyrin IX is a precursor of the ____ (3)
hemes, cytochromes, and chlorophyll.
Heme Synthesis - Seventh Step
-> Protoporphyrinogen oxidase found in ____
inner mitochondrial membrane.
Heme Synthesis - Seventh Step
-> Protoporphyrin IX is a precursor of the ____ (3)
hemes, cytochromes, and chlorophyll.
Heme Synthesis - Seventh Step
-> Variegate porphyria is caused by ____
mutations in protoporphyrinogen oxidase.
Heme Synthesis - Seventh Step
-> In this reaction, protoporphyrin IX is formed from protoporphyrinogen IX by ____.
oxidation
What happen in Heme Synthesis - Final Step (8th step)?
In the final step, ferrous iron is inserted in the middle of the porphyrin ring.
Heme Synthesis - Final Step
-> Identify molecule(s)/ enzyme(s)?
1/ Protoporphyrine
2/ Heme B
3/ Ferrochelatase
Heme Synthesis - Final Step
-> Where can you find Ferrochelatase?
in the inner mitochondrial membrane.
Heme Synthesis - Final Step
-> What happen to heme A, C, O?
Other hemes require additional modifications.
Heme Synthesis
-> Identify
1/ ALA synthetase
2/ ALA Dehydrogenase
3/ Porphobilinogen deaminase
4/ Uroporphyrinogen III synthetase
Heme Synthesis
-> Identify
1/ Coproporphyrinogen III Oxidase
2/ Protoporphyrin III Oxidase
3/ Ferrochelatase
Heme Synthesis
-> Identify
1/ Porphobilinogen
2/ Hydroxymethyl bilane
3/ Uroporphyrinogen III
4/ Coproporphyrinogen III
Heme Synthesis
-> Identify
1/ Protoporphyrinogen III
2/ Protoporphyrin IX
3/ Heme
Heme Synthesis
-> Identify
Globin chains
Where do Porphyrias arise?
1/ From deficiencies in heme synthesis enzymes and accumulation of porphyrins.
2/ From heavy metal poisoning or drugs affecting some liver enzymes.
Can liver disease cause porphyria?
Yes
Porphyrias
-> When do skin problems arise?
when porphyrins accumulate in skin and fluoresce.
Porphyrias
-> When do skin problems arise?
when porphyrins accumulate in skin and fluoresce.
Iron Transport and Storage
-> Characteristics of iron in metabolism
1/ Iron is a limiting micro-nutrient.
2/ Needed for heme, enzymes, electron transport, oxygen transport
3/ Can gain or lose electrons, depending on oxidative state
4/ Very reactive and toxic to cells
5/ Can create radicals with ROS in the cell via the Fenton reaction
What is Fenton reaction?
Iron create radicals with ROS
The role of Iron-binding proteins
Iron-binding proteins perform functions and help keep iron from doing cellular harm.
List Storage proteins for iron
- Intracellular ferritin
- Extracellular - lactoferrin (secretory fluids), transferrin (plasma)
- Enzymes - catalase, aconitase
- Electron transport - complexes I, II, III, IV, cytochrome C
- Other - hemoglobin, myoglobin
Which one is the intracellular storage protein of iron?
Ferritine
Which one is the extracellular storage protein of iron?
lactoferrin (secretory fluids), transferrin (plasma)
What is Transferrin?
a glycoprotein in blood plasma carrying iron.
Iron Transport and Storage
-> Characteristics of transferrin
- Small pool in body, but very rapid iron turnover
- Extremely high affinity for iron each one
carries two Fe3+ atoms.
Iron Transport and Storage
-> The role of Transferrin
- Delivers iron from duodenal absorption centers and macrophages to all tissues.
- Carries iron into cell by binding to membrane- bound transferrin receptor.
Iron Transport and Storage
-> How does transferrin work? (4 steps)
- Moved into cell by receptor-mediated endocytosis of both
- Proton pumps lower pH and transferrin releases iron in cell.
- Free iron in cell is taken up by ferritin
- Transferrin and receptor recycled back to
cell surface.
Iron Transport and Storage
-> What is Ferritin?
an intracellular protein complex (24 subunits) found in all kingdoms of life.
Iron Transport and Storage - Ferritin
-> Low serum ferritin linked to ___
anemia
Iron Transport and Storage - Ferritin
-> What is Hemosiderin?
a large complex of dysfunctional ferritins and other materials sequestering iron.
Iron Transport and Storage - Ferritin
-> Iron stored in ____ state in ferritin
Fe3+
Iron Transport and Storage - Ferritin
-> Which enzyme does ferritin contain?
Ferroxidase
Iron Transport and Storage - Ferritin
-> Iron stored in ____ state in ferritin
Fe3+
Iron Transport and Storage - Ferritin
-> Ferroxidase within ferritin catalyzes which reaction?
- Ferroxidase within ferritin catalyzes conversion
4Fe2+ + 4H+ +O2 <=> 4Fe3+ + 2H2O
Iron Transport and Storage
-> What are Transferrin receptors?
transmembrane glycoproteins.
Iron Transport and Storage
-> _____ increase expression of transferrin receptor.
Low cellular iron levels
Iron Transport and Storage
-> _____ enhances transferrin uptake by cells.
(which enzyme?)
Secreted glyceraldehyde 3-phosphate dehydrogenase
Iron Response Element - IRE is a secondary structure in ___
mRNA
Iron Response Element - IRE is found in _____ (3)
ferritin and transferrin receptors and other iron metabolizing proteins
Iron Response Element - IRE is bound by ____
a protein called IRE binding protein (IRE-BP)
What can IRE Binding Protein - IRE-BP bind to?
Can bind either to IREs in mRNA or to iron, but not both
If iron concentration is high, what happen to the binding of IRE Binding Protein - IRE-BP?
If iron concentration is high, IRE-BP binds to iron and not IRE.
If iron concentration is LOW, what happen to the binding of IRE Binding Protein - IRE-BP?
If iron concentration is low, IRE-BP is free to bind to IRE.
Iron Response Element
-> Identify
Regulation of Iron Proteins - ferritin
-> What happen when [iron] is low?
- Low iron - IRE-BP free to bind IRE
- IRE-BP binds ferritin IRE blocks translation
- Thus, low iron turns off ferritin production.
Regulation of Iron Proteins - ferritin
-> What happen when [iron] is high?
- High iron -> iron binds to IRE-BP
- IRE - BP can’t bind IRE of ferritin mRNA
- Ferritin translation proceeds
- Thus, in high iron, ferritin is synthesized to hold it.
Iron Transport and Storage - transferrin
-> What happen to Binding of IRE-BP to the transferrin receptor? (when iron high)
- at 3’ end of mRNA, IRE-BP binding to IRE protects against nuclease degradation
- When iron high, IRE-BP binds iron, can’t bind IRE of mRNA
- With no IRE-BP protection, transferrin receptor mRNA gets degraded.
- Thus, in high iron, no transferrin receptor is made.
Iron Transport and Storage - transferrin
-> What happen to Binding of IRE-BP to the transferrin receptor? (when iron low)
- When iron low, IRE-BP binds IRE of mRNA
- IRE-BP on mRNA protects against nuclease degradation.
- Transferrin receptor mRNA not degraded, so transferrin receptor made
- Thus, in low iron, transferrin receptor is made to bring iron into cell.
