Lect 10 Erythrocyte Biochemistry Flashcards
What is Erythropoiesis?
What are the stages?
When is majority of Hb synthesized?
RBC production
Hemocytoblast –> Proerythroblast -> Early Erythroblast –> Late Erythroblast –> Normoblast –> Reiculocyte –> Erythrocyte
Prior to extrusion of the nucleus
Adult Hb is a multi-subunit protein (tetramer) made up of what subunits?
Characteristics of Heme
- 2 a-globin chains & 2 B-globin chains
-
Heme:
- One per subunit
- Has iron atom (ferrous: Fe2+)
- Carries O2
- Hydrophobic
Types of Hb
Embyronic composition? When are they gone?
Fetal composition?
Adult composition?
Which chromosomes have genes for subunit production?
- Embryonic:
- Hb Gower 1; Hb Gower 2; Hb Portland
- Week 8
- Fetal:
- HbF (a2y2)
- Adult
- HbA (a2B2)
- 16 & 11
How is HbF being used in Sickle Cell Anemia (HbS)?
Downsides?
Using hydroxyurea to induce HbF and address inflamation
Toxic chemotherapeutic agent
Which is the proximal histidine and what is it bound to?
Which is the distal histidine and what is it bound to?
O2 binding –> Conformational change –> Changes position of iron in plane of heme, which histidine moves with the iron?
F8 Histidine (Proximal) is bound to Heme
E7 Histidine (Distal) binds to O2 that is bound to iron in Heme
F8 (Proximal) Histidine is pulled down
What type of dissociation curve for myoglobin? Hemoglobin?
What is Cooperativity?
Myoglobin: Hyperbolic
Hemoglobin: Sigmoidal
Binding/Releasing one O2 to/from heme, facilitates further binding/releasing of O2
O2 Dissociation Curve (ODC): Bohr Effect (pH)
What is the change in pH from Lungs to actively respiring tissues?
How is binding affinity of Hb affected?
7.4 –> 7.2
Binding affintiy decreases as pH decreases
ODC: Modulation by 2,3-BPG
What is the affect on Hb by 2,3-BPG?
Reduces O2 affinity so gives up more oxygen to tissues
ODC: Modulation by Exercise
What is the difference in providing O2 to resting tissues and exercising tissues?
Drop in pO2 from 40 (rest) –> 20 (exercise) leads to increased oxygen offloading to tissues
ODC: Fetal (HbF) & Maternal (HbA) RBCs
What is the reason O2 flows from mother to fetus?
HbF has higher affinity for O2 (does not bind well to 2,3-BPG)
Distribution of Iron in Humans
What are the two types of storage iron?
Ferritin (H2O soluble)
Hemosiderin (H2O insoluble)
Iron Absorption, Storage, and Transport
How is Nonheme iron Fe3+ (plant products) and Heme iron Fe2+ (animal products) transferred to blood?
What are the storage forms and what type of iron is used?
- Converted to Fe2+ (Ferric Reductase/Dcytb) for Nonheme (Fe3+)
- Into enterocyte (Divalent Transporter 1/DMT1 on Apical)
- Transport into blood (Ferroportin on Basolateral)
- Fe2+ –> Fe3+ in blood (Ferroxidase / Cerruloplasmin / Hephaestin)
- Transported to tissues via Transferrin
- Fe3+ –> Ferritin –> Hemosiderin (Via degradation)
Transferrin Receptor (TfR) Mediated Endocytosis
How is Transferrin internalized and where is it taken?
What transports iron out of endosome?
Calthrin coated pits (endosomes) transport iron to mitochondria
DMT1
Causes of Iron Deficiency?
- Insufficient dietary iron
- Menstruation
- Aspirin overuse
- GI ulcers –> Blood loss
Hereditary Hemochromatosis
What is it?
What is the normal total body iron level and what is level in those with H.H.?
Organ dysfunction due to iron overload
3-5g normal & 15g H.H.
Folate Metabolism
Carbon side chain of serine transferred to THF to form N-methylene-THF, what can this then give rise to?
What else can it produce and what is required to reverse it?
What is a third potential product and its application?
- Carbon of N-methylene-THF –> dUMP –> dTMP (DNA synthesis) + DHF (dihydrofolate reductase) –> THF
- N-methylene-THF can also be converted to N-methyl-THF (trapped - requires Vit B12/Cobalamin)
- N-methenyl-THF which can be used in de novo purine biosynthesis
