Lecture 6: Erythrocyte Biochemistry Part 1

Question 1

What is the pathway of erythropoiesis?

Answer 1

HSC > committed cell > ribosome synthesis (phase 1) > Hb accumulation (phase 2) > nucleus ejection (phase 3) > erythrocyte

Question 2

What does adult Hb contain?

What does fetal Hb contain?

Answer 2

Adult: Hb A (2a, 2B or 2D)
Fetal: Hb F (2a2Y)

Question 3

What is the structure of adult Hb?

Answer 3

Each globin chain has a heme in the center (iron + porphyrin ring) that carries the O2

Question 4

What happens to Hb structure after O2 binds?

Answer 4

Iron molecule aligns with plane of the porphyrin ring > pulls proximal His of globin chains > conformational change > cooperativity

Question 5

What is the role of the distal His residue of the globin chain?

Answer 5

Stabilizes bound O2

Question 6

Why does myoglobin have a hyperbolic and hemoglobin a sigmoidal dissociation curve?

Answer 6

Myoglobin has higher O2 affinity and no cooperativity

Hemoglobin has lower O2 affinity and exhibits cooperativity

Question 7

What does cooperativity mean?

Answer 7

Binding/removal of O2 from one globin chain = easier binding/removal to other globin chains&raquo_space;> sigmoidal curve

Question 8

How does pH change affect the ODC?

Answer 8

Low pH in tissues = right shift (Bohr effect) in the tissues

Question 9

How does 2,3, BPG bind to affect the ODC?

Answer 9

It binds to Hb, reducing affinity to O2 = right shift

Question 10

How does exercise affect ODC?

Answer 10

Decrease pO2 = Hb releases O2 to tissues = right shift

Question 11

What is the difference between fetal and maternal Hb?

Answer 11

Fetal Hb has higher affinity to O2 and does not bind 2,3, DPG (leftward ODC compared to adult)

Question 12

Sickle Cell anemia
Cause
Tx

Answer 12

• 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

Question 13

What major physiological processes does Iron participate in?
At what level is body iron regulated?

Answer 13

O2 transport via Hb and ETC as part of cytochrome

By controlling absorption

Question 14

What are the major storage proteins for iron?

Answer 14

Ferritin (binds ferric iron)

Hemosiderin (product of ferritin breakdown)

Question 15

Draw the pathway of Iron absorption

Answer 15

Ok

Question 16

How is transferrin processed in the cells?

Answer 16

Binds TfR > taken up by coated pits > forms low pH endosome > transferrin removed from TfR (which is recycled) > transported into MT by DMT-1

Question 17

What molecule regulates the absorption of iron and how does it do so?

Answer 17

Hepcidin binds to ferroportin transporter in the enterocyte > lysosomes degrade the gate > no gate = no entry

Question 18

What regulates Hepcidin production?

Answer 18

HFE (human homeostatic iron regulator protein (HFE)

Question 19

What does it mean to be iron deficient or overloaded?

Answer 19

Refers to absorption of iron, not necessarily levels

Question 20

Iron deficiency
Possible causes
What type of anemia results?
Treatment

Answer 20

• insufficient diet or absorption, bleeding, aspirin overuse
• Hypochromic microcytic anemia
• iron supplements

Question 21

Hereditary Hemochromatosis/HH
Causes
Clinical

Answer 21

• 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)

Question 22

What two things is RBC production dependent on?

Answer 22

Folate and cobalamin (vit. B9 and b12)

Question 23

Megaloblastic Macrocytic Anemia
Cause
Clinical (how do blood cells look?)

Answer 23

• B9 and B12 deficiency

- Large erythrocytes >100 fL (but normal Hgb levels), large erythroblasts in bone marrow, hypersegmented neutrophils

Question 24

What makes up the structure of folate?

Answer 24

Pteridine ring, PABA and glutamate residues

Question 25

Draw the pathway for folate metabolism

Answer 25

Ok

Question 26

Why is folate important for RBC maturation?

Answer 26

Important for purine and thymine synthesis. Deficiency causes megaloblastic macrocytic anemia

Question 27

How is folate absorbed?

Answer 27

In jejunum, reduced to and circulates as N5-methyl THF

Question 28

Why is B12 important in RBC maturation?

Answer 28

It converts circulating folate to active THF by removing the methyl (avoid folate trap) and also using it for purine and pyrimidine synthesis

Question 29

What is methotrexate?

Answer 29

Analog of DHF that inhibits DHF reductase

Chemo drug that prevents DNA synthesis in cancer cells

Question 30

What is the usual cause and effects of Vit. B12 deficiency?

Answer 30

Lack of Intrinsic factor, causes megaloblastic macrocytic anemia

Question 31

What is the role of intrinsic factor in B12 absorption?

Answer 31

Eaten b12 binds to R-binder, IF replaces R-binder and transports B12 to bloodstream. IF-B12 is taken up by cells for use

Question 32

What is the usual cause of pernicious anemia?

Answer 32

IF deficiency (can’t absorb B12), type of MM Anemia

Question 33

What is a Schilling test and how is it performed?

Answer 33

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