Erythrocyte Biochemistry Flashcards
What makes R-Binder proteins?
Gastric mucosa cells in the stomach
Where does nonheme iron come from?
Plant products
Oxygen Dissociation curve for hemoglubin
Sigmoidal curve
The uptake of transferin by cells is done by what process?
Receptor mediated endocytosis via transferin receptor (TfR).
B12 deficiency is often caused by what.
What impact can this deficiency have?
Dietary lack is not often the cause, 3 ug dailly allowance
85% of cases are the lack of a protein called intrinsic factor.
Causes megaloblastic anemia because of the decrease of N5,10-methylene-THF and on DNA synthesis
What is the efficiency of hemoglobin in delivery of oxygen to from lung to tissue.
Drops from 7.4 to 7.2 pH
66%
Describe B12 Absorbtion
B12 binds to R-binder proteins in somach
Degraded by proteases in the dudenom releasing B12
Intrinsic factor carries B12 to ileum where it is absorped by receptors.
In what form foes ferritin store iron?
As Fe3+
What converts Fe3+ in non-heme iron to Fe2+
Ferric Reductase
What is the generation of erythrocytes known as?
Erthropoiesis
Where does heme iron come from?
Animal products
Why is HbF in the fetus higher in affinity the HbA in the mother?
Oxygen travels mother to fetus.
HbF does not bind well to 2,3-BPG so this cannot decrease its affinity as much.
What happens to affininty for oxygen as pH decreases. How does this work and what is this effect called?
O2 affinity decreases as pH decreases
His 146 picks up H+ from tissue and causes a conformational change in Hg.
Called the Bohr Effect
How do internalized endosomes get transferin to the mitchondira for heme synthesis?
Clatherin coated endosome transiently docks and DMT1 helps to facilitate the transport of iron out of the endosome.
2,3-Biphosphoglycerate has what effect on O2?
Reduces the affinity of O2 so Hb gives up more O2 to tissues
What form of folate is dietary?
Dihydrofolate (DHF)
What is portential therapy for sickle cell anemia?
What are the worries in this?
Changing HbS to HbF using hydroxyurea
This is a toxic chemotherapeutic agent
What cell features are observed in megaloblastic anemia?
Large erythrocytes >100 fL (normal is 80-100) (same ratio of hematocrit)
Large erythroblasts
Hyper-segmented neutrofills (more then 5 lobes, 3-4 normal)
How is B12 transported into and throughout the blood
Intrinsic factor bound to cobalin is taken up by receptor-mediated endocytosis.
Cobalin circulates through the blood by transcobalamin
Stem cells and commited cells of erthropoiesis
Hemocytoblast
Proerythroblast
What can result as part of Hereditary Hemochromatosis?
Organ dysfunction due to iron overload: cirrhosis, arthritis, endocrinopathy, skin pigmentation, cardiomyopathy
What is the function of THF?
Transfers carbon units from donors to acceptors
Is vital for DNA synthesis
What transports iron in the blood?
Transferrin
What enzyme refuces folate to DHF and THF?
Dihydrofolate reductase
Oxidizes NADPH to NADP
Add 2 electons + hydrogens at a time
Describe folate metabolism.
THF to N5,10-methylene-THF as the carbone side chain of a serine is transfered
Carbon of N5,10-methylene-THF is transfered to deoxyuridylate (dUMP) to form deoxythmidylate (dTMP) during which DHF is made
How does positive cooperativity work?
The binding of O2 to Fe of a globin subunit pulls the proximal F8 histindine down ==> this pulls the globin FG-helix and changes the interaction with the other globin chain in Hb
What converts free iron to Fe3+?
Hephaestin/cerruplasmin
Dysregulation of iron uptake and export by enterocyte
15g of Total iron body weight
What is the disease and treatment?
Hereditary Hemochromatosis
Blood letting
What is the fetal hemoglubin and when does it peak?
Hb F (a2g2)
Gamma chain peaks right before birth and then subsides.
Alpha continually increases up untill birth where it levels off.
What makes Intrinsic factor?
Pariatal cells in the stomach.
How does regulation of hepciden work?
Tf-Fe bind s Tfr1
This causes Hfe to bind to Tfe2
Tf2 then upregulats signal transduction of hepcidin
What takes up Fe2+ in the enterocyte.
Divalent transporter-1 (DMT1)
What percentage of Iron is stored and in what forms?
27%
Ferritin and hemosiderin
What takes Fe 2+ out of the cell?
Ferroportin
How is pernacious anemia tested?
Serum folate <3 ng/ml
Serum B12 <350pg/ml
Coduct Schilling Test
Distal hisitidine location. What does it stabilize binding of?
E7 binds to the iron between the heme and distal histidine
Binds with oxygen.
How does the comformation of hemoglubin change when oxygen bind?
A 0.4 Å change pulls down the proximal F8 histidine of Hb and
changes interaction with associated globin chain
What would a mutation in Hfe cause?
Hemotomachromatosis
Can no longer bind to Tf2 and cause upregulation of hepcidin, therefore it would lead to overload of iron in blood
Oxygen Dissociation curve for Myoglubin
Hyperbolic curve
Why is cobalamin essential to overcoming the folate trap?
Vitamin B12 removes a methyl group from N5-methyl-THF to make methyl-cobalalmin (B12-CH3) and THF
How do you conduct the Schilling test?
- 5-1.0 ug oral dos of 57Co-labled B12 (simultaneously saturating all cobalim receptor s with 1,000ug injection of B12).
- If radioactive urine after 24 hours = healthy and diet is the problem (STOP)
- If not radioactive urine after 24 hours = pernacious anemia
(GO ON TO 3.)
- Repeat with B12 doses given with Intrinsic factor, if radioactive its due to a lack of intrinsic factor.
What are the adult hemogblubins
Hb A (a2b2) 97%
Hb A2 (a2g2) 3%
Beta increases more rapidly after birth and to a greater degree then gamma
What are the embryonic hemeglobins and when are they gone?
Hb Gower 1
Hn Gower 2
Hb Portland
What are the tetramer chains in Hemoglubin
2 alpha-globin chains
2 beta-globin chains
What is added to THF to create a C-FH4 donor?
Addition of CH2
Where is folate absorbed and where is it absorbed?
The jejunum
Liver stores 5 to 10 mg folate which can last 2 to 6 months
Peptide that binds to ferroportin causing internalization and proteolysis of ferroportin.
Explain it’s regulation of iron homeostasis
Hepcidin
Iron High = Hepcidin Up = Ferroportin Down
Steps of the developmental pathway in erythropoeisis.
Early erythroblast -> Late erythroblast (Ribosome synthesis)
Late erythroblast -> Normoblast (Hemeoglubin accumulation)
Normoblast -> Retulocytes (Ejection of nucleus)
Retulocytes -> Erythrocytes
What does hepcidin overexpression result in?
What about underexpression?
Low plasma iron levels
Overloaded plasma iron levels.
What causes hypochromic microcytic anemia?
Iron Defieciency
Insufficient dietary iron
Menstration
Aspirin overuse
Ulcers of GI tract (Blood loss)
Treatment - dietary iron supplementation
Why is B12 needed in folate acid metabolism?
N5-methyl-THF requires cobalamin to transfer a single methylene group to dUMP to make dTMP (for DNA synthesis)
Stuck as N5-methyl-THF known as the folate trap
Where is the proximal hisitidine located at?
F8 Histidine bound to heme
What can HbS cause in hemoglubin?
Polymerization
Why is methene-THF important and what does it do?
Synthesis of nucleotides through addition of methylene
THF grabs methyl groups using 2 Nitrogens
What reduces Fe3+ to Fe2+ on cell surface?
Dcytb (duodenal cytochrome b) aka Ferric Reductase
What is a healthy iron body weight
3 to 5g
What is pernacious anemia
Lack of intrinsic factor results in megaloblastic macrocytic anemia due to lack of B12.
Results in:
Gastric mucosa destroyed through auto-immune mechanism Decreased intrinsic factor
How does RBC production depend of folate and B12
It does so for DNA synthesis.
If there is a decrease in this it can result in megaloblastic anemia.
