Lecture 6: Erythrocyte Biochemistry Flashcards
How does the structure of hemoglobin differ between adult and fetal forms?
Adult: 2 alpha and 2 beta globin chains
Fetal: 2 alpha and 2 gamma globin chains
What state is the iron atom in a heme?
Fe 2+ (ferrous)
When oxygen binds to a heme group, what happens to iron ion?
Iron movies into plane of heme and pulls down the proximal histidine of hemoglobin
-oxygen forms a hydrogen bond with histidine
What type of oxygen saturation curve is seen with a myoglobin?
Hyperbolic curve
-only 1 peptide
What type of oxygen saturation curve is seen with a hemoglobin?
Sigmoidal curve
-due to interaction between four globin subunits
Describe positive cooperativity.
The binding of one oxygen molecule to hemoglobin makes it easier to bind to other oxygen molecules
-change in one globulin subunit induces a change in another subunit
What is the Bohr Effect?
Decreased affinity of hemoglobin for oxygen
-releases oxygen (want this in tissues)
What changes are seen in Bohr Effect?
1) Decrease in pH (increase in H+)
2) Increase in 2,3-BPG (tells Hb to give up oxygen)
3) Exercise (drop in partial pressure of oxygen)
Why is affinity for oxygen higher in fetal red cells compared to maternal red cells?
Fetus needs to get oxygen from mother
- fetal Hb does not bind well to 2,3-BPG
- left shift
In sickle cell disease, where is the mutation?
Amino Acid position #6 in beta globulin
- glutamic acid changes to valine
- polymerization of hemoglobin
Where is iron stored?
- Cells that line intestine
- Liver
- Spleen
- Bone Marrow
How is heme iron stored?
1) Fe 2+ (heme) enters enterocyte (intestinal cell) and converted into Fe 3+ via ferroxidase
2) Stored as ferritin and can be degraded into hemosiderin
How is non-heme iron stored?
1) Fe 3+ is converted into Fe 2+ in the intestinal lumen via ferric reductase in presence of Vit C
2) Fe 2+ enters enterocyte via DMT1
3) Fe 2+ is converted into Fe 3+ via ferroxidase
4) Stored as ferritin and can be degraded into hemosiderin
How does iron leave the enterocyte?
1) Must be in Fe 2+ state
2) Leaves basolateral side via ferroportin.
3) Converted to Fe 3+ via ferroxidase
4) Transferrin transports Fe 3+ to liver, spleen, bone marrow
Ferroportin requires what for its function?
Hephaestin
Ferroportin levels and iron content in the body are regulated by?
Hepcidin
Describe the process of transferrin uptake.
1) Uptake via receptor-mediated endocytosis via transferrin receptor
2) Internalized via clathrin pits
3) Transferrin is released in endosome due to low pH
4) Iron is uptaken in mitochondria via DMT1
What happens when hepcidin binds to ferroportin?
Internalization of ferroportin and subsequent degradation in lysosomes
What regulates levels of hepcidin?
Transferrin and its receptor: Human homeostatic iron regulator protein (HFE)
- High levels of iron (transferrin)n–> hepcidin expression up –> low levels of ferroportin –> low iron absorption levels
- Low levels of iron (transferrin) –> hepcidin expression down –> high levels of ferroportin –> high iron absorption levels
What can cause iron deficiency?
- Insufficient dietary iron
- Insufficient absorption
- Excessive blood loss via menstruation
- Overuse of aspirin
- Ulcers of GI tract
What can iron deficiency cause?
Hypochromic microcytic anemia
What can iron overload cause?
Hereditary Hemochromatosis
- accumulation of iron in heart, liver, and pancreas, which can cause severe issues
- autosomal recessive in HFE gene
- 15 g of iron instead of normal 3-5
RBC production is dependent on what?
Folate Vitamin B12 (cobalamin)
What can a deficiency in folate and vitamin B12 cause?
Megaloblastic anemia
- diminished synthesis of DNA
- large RBC
What is the active form of folate?
Tetrahydrofolate (THF)
What is the role of THF?
Synthesis of purines and thymine
Where is folic acid absorbed?
Small intestine (jejunum)
Where is folic stored?
Liver
In dietary sources, folate is in what form?
DHF
In the intestines, folate acid is reduced to what form?
N5-methyl-THF
What enzyme converts FH2 (DHF) into FH4 (THF)
Dihydrofolate Reductase
What inhibits dihydrofolate reductase?
Methotrexate
What is an important component of Vit B12?
Cobalt
What does Vit B12 do?
Removes methyl group from N5-methyl-THF to generate FH4 (THF)
Where is Vit B12 found?
Animal products
-made by microorganisms
What is the main cause of Vit B12 deficiency?
Lack of protein: intrinsic factor
How is Vit B12 absorbed?
- Dietary Vit B12 binds to R-binder proteins
- Intrinsic factor carries B12 to ileum and it is released into blood stream from there by transcobalamin II
- Intrinsic Factor-cobalamin complex taken up by cells via receptor-mediated endocytosis
What is pernicious anemia?
Megaloblastic macrocytic anemia
-Vit B12 deficiency due to lack of intrinsic factor
How do you test for pernicious anemia?
1) Oral dose radioactive Vit B12
- if it is seen in urine 24 hours later, then it has been absorbed
2) If radioactive Vit B12 not seen in urine, oral dose of radioactive Vit B12 + Intrinsic factor
- if it is seen in urine 24 hours later, then pernicious anemia is due to lack of intrinsic factor
