Lecture 6: Erythrocyte Biochemistry Part 1 Flashcards
What is the pathway of erythropoiesis?
HSC > committed cell > ribosome synthesis (phase 1) > Hb accumulation (phase 2) > nucleus ejection (phase 3) > erythrocyte
What does adult Hb contain?
What does fetal Hb contain?
Adult: Hb A (2a, 2B or 2D)
Fetal: Hb F (2a2Y)
What is the structure of adult Hb?
Each globin chain has a heme in the center (iron + porphyrin ring) that carries the O2
What happens to Hb structure after O2 binds?
Iron molecule aligns with plane of the porphyrin ring > pulls proximal His of globin chains > conformational change > cooperativity
What is the role of the distal His residue of the globin chain?
Stabilizes bound O2
Why does myoglobin have a hyperbolic and hemoglobin a sigmoidal dissociation curve?
Myoglobin has higher O2 affinity and no cooperativity
Hemoglobin has lower O2 affinity and exhibits cooperativity
What does cooperativity mean?
Binding/removal of O2 from one globin chain = easier binding/removal to other globin chains»_space;> sigmoidal curve
How does pH change affect the ODC?
Low pH in tissues = right shift (Bohr effect) in the tissues
How does 2,3, BPG bind to affect the ODC?
It binds to Hb, reducing affinity to O2 = right shift
How does exercise affect ODC?
Decrease pO2 = Hb releases O2 to tissues = right shift
What is the difference between fetal and maternal Hb?
Fetal Hb has higher affinity to O2 and does not bind 2,3, DPG (leftward ODC compared to adult)
Sickle Cell anemia
Cause
Tx
- Glu to Val (hydrophobic) mutation causes Hb to clump together and form C shaped RBCs, blood can’t effectively squeeze through capillaries due to its shape
- Hydroxyurea replaces defective hemoglobin with fetal hemoglobin
What major physiological processes does Iron participate in?
At what level is body iron regulated?
O2 transport via Hb and ETC as part of cytochrome
By controlling absorption
What are the major storage proteins for iron?
Ferritin (binds ferric iron)
Hemosiderin (product of ferritin breakdown)
Draw the pathway of Iron absorption
Ok
How is transferrin processed in the cells?
Binds TfR > taken up by coated pits > forms low pH endosome > transferrin removed from TfR (which is recycled) > transported into MT by DMT-1
What molecule regulates the absorption of iron and how does it do so?
Hepcidin binds to ferroportin transporter in the enterocyte > lysosomes degrade the gate > no gate = no entry
What regulates Hepcidin production?
HFE (human homeostatic iron regulator protein (HFE)
What does it mean to be iron deficient or overloaded?
Refers to absorption of iron, not necessarily levels
Iron deficiency
Possible causes
What type of anemia results?
Treatment
- insufficient diet or absorption, bleeding, aspirin overuse
- Hypochromic microcytic anemia
- iron supplements
Hereditary Hemochromatosis/HH
Causes
Clinical
- HFE mutation (autosomal recessive) leading to iron overload, accumulates in viscera
- results in cirrhosis, liver cancer, DM, arthritis or heart failure, 15 g total body iron (normal 3-5 g)
What two things is RBC production dependent on?
Folate and cobalamin (vit. B9 and b12)
Megaloblastic Macrocytic Anemia
Cause
Clinical (how do blood cells look?)
- B9 and B12 deficiency
- Large erythrocytes >100 fL (but normal Hgb levels), large erythroblasts in bone marrow, hypersegmented neutrophils
What makes up the structure of folate?
Pteridine ring, PABA and glutamate residues
Draw the pathway for folate metabolism
Ok
Why is folate important for RBC maturation?
Important for purine and thymine synthesis. Deficiency causes megaloblastic macrocytic anemia
How is folate absorbed?
In jejunum, reduced to and circulates as N5-methyl THF
Why is B12 important in RBC maturation?
It converts circulating folate to active THF by removing the methyl (avoid folate trap) and also using it for purine and pyrimidine synthesis
What is methotrexate?
Analog of DHF that inhibits DHF reductase
Chemo drug that prevents DNA synthesis in cancer cells
What is the usual cause and effects of Vit. B12 deficiency?
Lack of Intrinsic factor, causes megaloblastic macrocytic anemia
What is the role of intrinsic factor in B12 absorption?
Eaten b12 binds to R-binder, IF replaces R-binder and transports B12 to bloodstream. IF-B12 is taken up by cells for use
What is the usual cause of pernicious anemia?
IF deficiency (can’t absorb B12), type of MM Anemia
What is a Schilling test and how is it performed?
Tests b12 and folate levels
Part 1: Pt given radioactive B12. Urine checked for B12 presence. If absent, B12 isn’t absorbed = pernicious anemia
Part 2: Pt given radioactive B12 + IF. Urine checked for B12. If now present, that means adding IF was missing in patient
