Erythrocyte and Heme Biochem Flashcards
List the RBC factoids:
RBCs live for 120 days
we produce 2.4 million per second
and adult has 2 lbs of Hb
How do you get from stem cell to erythrocyte?
Hemocytoblast - Proerythroblast - Early erythroblast - late erythroblast - normoblast - reticulocyte - erythrocyte
*note: majority of Hb is synthesized before extrusion of nucleus from the normoblast to become reticulocyte (small amount made in reticulocyte)
Types of Hb
Fetal: Hb F (alpha2, gamma2), 0.5%
Adult: Hb A (alpha2, beta2), 97% Hb A2(alpha2, beta2), 3%
What is the structure of adult hemoglobin?
Multi subunit protein (tetramer) - 2 alpha globin chains, 2 beta globin chains + one heme subunit with a ferrous ion
What happens to Hb when oxygen binds?
The iron ion lies slightly outside the plane of porphyrin in heme. Upon oxygen binding, it moves into the plane of the heme. This 0.4 Å change pulls down the proximal histidine of Hb and changes interaction with the associated globin chain.
Myoglobin displays a _________ dissociation curve.
hyperbolic
Hemoglobin displays a __________ dissociation curve, due to cooperativity between globin subunits.
sigmoidal
What is positive cooperativity?
Binding of one molecule of O2 to one heme, facilitates the binding of an O2 to another heme
The binding of O2 to Fe of a globin subunit pulls the proximal F8 histidine down
This pulls on the globin FG-helix and changes the interaction with the other globin chains in Hb
Conformational change in one globin subunit induces a conformational change in another subunit in Hb
How does 2,3-BPG effect Hb?
reduces O2 affinity so Hb guves up more O2 to tissues; signal to Hb to let go of O2
What is the Bohr effect?
O2 and H+, produced by actively respiring tissues, enhance O2 release by hemoglobin. pH of actively respiring tissues drops from 7.4 to 7.2. As pH decreases, binding affinity of Hb for O2 decreases. Histidine (His 146) picks up H+ from tissue and changes Hb conformation to favor release of O2. CO2 and H+ are thus allosteric effectors of hemoglobin.
How is fetal Hb different than adult?
Fetus needs Hb that has higher affinity for O2 than maternal Hb •Fetal Hb is HbF (alpha2, gamma2) •Maternal Hb is HbA (alpha2, beta2) •O2 flows from mother to fetus •HbF does not bind well to 2,3-BPG •Therefore, has higher affinity for O2
Describe the Hb in sickle cell anemia
mutation in amino acid position #6 in beta globin chain, glutamic acid changes to valine causing polymerization of Hb
sickled RBCs are thus formed that impede circulation and cause hemolytic anemia
Iron factoids include:
- Iron readily exchanges electrons; ideal catalyst for oxidation-reduction reactions (exists in ferrous and ferric states)
- plays a role in oxygen transport
- also ETC
- iron is regulated by modulating its absorption
What is the distribution of Iron in humans:
- most in hemoglobin ~67%
- Stored iron: ~27% (stored in cells that line the intestines, liver, spleen, and bone marrow)
- ferritin: a protein that binds to ferric iron
- hemosiderin: product of ferritin breakdown
Describe iron absorption, storage, and transport
Heme iron (Fe2+) is easily absorbable. Enters enterocyte, oxidized to Fe3+ by Ferroxidase aka Cerruloplasmin.
- Stored in the form of ferritin and its degradation product Homosiderin.
- Non-Heme iron (Fe3+)(plant products) difficult to absorb. Converted to Fe2+ by ferric reductase aka Dcytb (duodenal cytochrome-like b protein) in presence of vitamin C.
- Fe2+ enters enterocyte via Divalent transporter-1 (DMT1) •Either converted to Fe3+ by Ferroxidase aka Cerruloplasmin for storage or exported out of enterocyte by ferroportin.
- Ferroportin requires Hephaestin for its function
- Ferroportin levels regulated by Hepcidin
- Once in blood Fe2+ is converted to Fe3+ by ferroxidase. Fe3+ gets bound to Transferrin for transport to target tissues.
Describe transferrin receptor mediated endocytosis
- Uptake of Transferrin occurs by receptor-mediated endocytosis via transferrin receptor (TfR)
- Internalized via clathrin coated pits into endosomes
- Low pH of endosome releases transferrin from its receptor
- Endosome transiently docks on the mitochondria and transfers iron directly to mitochondria via DMT1
How does Hepcidin regulate iron homeostasis?
Iron content in body regulated by modulating its absorption – by peptide hormone Hepcidin
- Hepcidin is a 25 amino acid peptide made by liver and regulated by Human homeostatic iron regulator protein (HFE)
- Exerts its regulatory effect by binding to ferroportin
- Binding of Hepcidin to Ferroportin causes internalization of Ferroportin and its subsequent degradation in lysosomes
What are some causes and effects of iron deficiency?
Insufficient dietary iron Insufficient absorption Excessive blood loss via menstruation Overuse of Aspirin Ulcers of GI tract (blood loss)
Causes hypochromic microcytic anemia
Treatment - dietary iron supplementation
What are some causes and effects of iron overload?
Increased absorption that accumulates in heart, liver, and pancreas;
Causes liver cirrhosis, hepatocellular carcinoma, diabetes, arthritis, and HF.
HH or hereditary hemochromatosis is autosomal recessive, mutations in HFE; treatment is chelators and blood letting
Deficiency in folate and B12 can cause what?
megaloblastic macrocytic anemia due to diminished synthesis of DNA in developing RBC in bone marrow
- RBC volume increased
- Marrow shows large erythroblasts termed megaloblasts and hyper segmented neutrophils
