Lecture 11: Hemoglobin Flashcards
What increases the function of hemoglobin?
2-3 BPG, H+, and HbF
List the global chains that are beta-like chains
AND what chromosome are they found on?
epsilon
gamma
delta
beta
Chromosome 11
Describe alpha thalassemias
both alpha genes; depletion of 1,2,3,4
affects the production of fetal and adult Hb
Describe the levels of 2,3 BPG in the lungs and in the active tissues
lungs has a low 2,3 BPG so that there is a high affinity for oxygen (leads to R form) so that the Hb takes up oxygen
tissues have a high level of 2,3 BPG which results in the T form, and makes the Hb release the O2 into the tissues
List and describe the 4 classic types of alpha-thalassemias
- alpha + thalassemia: 1 alpha gene is deleted which leads to a silent hematologic phenotype (-a/aa)
- alpha-thalassemia trait: 2 alpha genes deleted which leads to a low mean cell volume, low mean cell Hb with normal fetal and HbA2
(-a/-a pr –/aa) - HBH- 3 alpha genes are affected (-a/–); leads to severe anemia
- Hydrops fettles with Hb Bart’s- both alpha genes are completely inactivated (–/–)
Describe the positive cooperativity that is involved in hemoglobin/ O2 binding?
as soon as one O2 molecule binds, it increases the affinity of the next O2 molecule binding through the pulling of the proximal F* histidine
Which form (T or R) does 2,3-BPG stabilize?
T form; which causes a low affinity in the Hb which releases oxygen
What causes the sigmoidal shape of hemoglobins oxygen dissociation curve?
interactions between the subunits
Describe embryonic hemoglobins
-expressed in the yolk sac until 8 weeks
Describe sickle cell anemia in detail
- HbS is caused by an amino acid switch at amino acid position 6 and there is a substitution; glutamic acid for valine
- causes polymerization of hemoglobin which causes a sickle shaped RBC which is hard for the oxygen to bind
What are the 4 global chains that are in the normal adult?
alpha
beta
delta
gamma
Describe the role of 2,3 BPG in active tissues
there is a lot of it present in active tissues that causes the hemoglobin to let go of the O2 by binding to the central pore of the deoxyhemoglobin
Describe what happens when the oxygen binds to hemoglobin in regards to structure
- changes the position of the iron atom and moves into the plane of the heme
- this action pulls the F8 proximal histidine which is attached to the globulin change; which contribute to function
Describe the characteristics of hydrops fetalis including the genetic cause and type of Hb made along with the clinical presentation.
caused by a COMPLETE inactivation of the alpha genes, causing the fetus to make gamma tetramer Hb, which has a high affinity for O2 (so the mothers oxygen is delivered to the fetus BUT it does not want to give it up, and therefore does not deliver it to the tissues)
This leads to severe hypoxia and still born or death shortly after birth
severe edema results and CHF; hepatosplenomegaly
Describe the T and R forms of Hb
T-tense (non-oxygenated)
R-relaxse (oxygenated)
Describe the structure of hemoglobin
multi-subunit protein that has a heme per subunit; which is able to carry oxygen
Describe the thalassemias
most common diseases : insufficient globulin chains produced;
can occur in alpha or beta
Describe HbA1c and talk about its relationship to diabetes
- caused by a post-translational modification of the globulin chain in which a glucose is added (irreversible)
- in people with diabetes (poorly controlled esp), if their blood sugars are high and uncontrolled, you would expect to see
Define HbH
with the lack of alpha subunits (due to thalassemia) there is an increase in beta tetramers
- alpha global synthesis is 25-35% normal levels
- hemolytic anemia
Describe fetal hemoglobin
made predominantly in the liver; in the fetus this is about 90-95% on the total Hb production
Describe beta thalassemia
- reduced B chains
- excess a chains which cause damage to RBCs which leads to anemia
can either be no B chain expression (major) or partial B expression (minor)
Define Hb Bart’s
result of alpha thalassemia which affects the fetus; there is an increase in gamma tetramers due to the decreased alpha
Describe 2,3 bisphophoglycerate (23 BPG)
intermediate by product of glycolysis
present in RBC at the same concentration of Hb; makes hemoglobin efficient
What is the predominant form of hemoglobin?
HbA which has 2 alpha and 2 beta subunits
Define myoglobin
monomer that is encoded by different genes. Has one Fe2+
STORES O2 (important in muscles) which hemoglobin is an O2 transporter
What are the 3 types of hemoglobin that are present in humans?
embryonic
fetal
adult
Describe the relationship between hemoglobin and pH (Bohr effect)
as the pH decreases, the affinity for O2 is also decreased; When an H+ is present, the amino acid will pick it up and that will change the conformation of Hb, releasing O2
Describe what 2,3BPG does to the oxygen dissociation curve
makes it sigmoidal and shifts it to the right
List the global chains that are alpha like chains.
AND what chromosome are they found on?
zeta
alpha
Chromosome 16
Describe adult hemoglobin
starts being produced after birth
newborn: 50-85% HbA, fully adult at 1 year
What is the function of erythrocytes?
transport oxygen from the lungs to the tissue
Describe erythropoiesis
2/3 of the hemoglobin is made prior to nucleation. The other third is made in the reticulocyte; globulin synthesis
Describe the heme group that is present in the hemoglobin
- gives blood color
- has an organic component (protoporphyrin) and an iron center
- has4 pyrrole rings that form a tetrapyrrole ring
- iron is at the center of this bonded to nitrogen atoms
Describe HbF
does not bind well to 23BPG which means a higher affinity for oxygen;
mostly present in the R form (high affinity for O2)
Describe Hydrops fettles with Hb Bart’s
make a gamma 4 Hb which is bad news
-stillborn or die a few hours after birth because no oxygen
they have a high affinity for O2 but are not able to drop it off in the tissues which leads to severe hypoxia and leads to CHF And edema
Describe the concept of tissue switching
During development, the fetal red blood cells are created in the liver, spleen, and yolk sac. BUT when the baby is born, it starts being made in the bone marrow
Describe the histidines that are present within hemoglobin…
- who is the most proximal histidine?
- who is the distal histidine?
- F8
2. E7 (binds the O2)
Describe carboxyhemoglobin
occurs when the heme binds to CO (210 times stronger than the O2 Hb bond)
causes a decreased transport of oxygen to the tissues
Describe the reversibility of the binding of oxygen
Once one is lost, there is an increased chance that the other subunits will also lose their oxygen
Which pair of globin chains makes up the majority of hemoglobin found in the normal human fetus? – A. a2b2 – B. a2g2 – C. a2d2 – D. z2b2 – E. a1g3
B
