Lecture 11 Flashcards
explain where the different percentages of hemoglobin are synthesized
65% of Hemoglobin is synthesized before the extrusion of the nucleus
the remaining 35% is made by the reticulocyte
what percentage of volume of erythrocytes does hemoglobin occupy? what percentage of protein synthesis in reticulocytes is devoted to globin synthesis?
33% (90% of the cell’s dry weight)
95% of all protein synthesis
During much of fetal life, what organ makes RBC’s? what occurs after birth?
The liver
RBC production switches to the bone marrow after a fetus is birthed (this is a time controlled process, so premature babies don’t switch for a while)
Describe the structure of hemoglobin in general (subunits and what each subunit has)
it is a multi-subunit tetramer composed of 2 alpha-globin chains and 2 other globin chains
Each subunit has it’s own heme group (iron) that can carry a molecule of O2
(so each hemoglobin tetramer can carry 4 O2 molecules)
State the chains that compose the 3 main types of hemoglobin that are found in an adult (include embryonic):
HbA:
HbA2:
HbF (fetal):
Embryonic Hb:
HbA: 2 alpha-globin chains and 2 Beta-globin chains
HbA2: 2 alpha-globin chains and 2 Delta-globin chains
HbF: 2 alpha-globin chains and 2 Gamma-globin chains
Embryonic Hb: 2 Zeta-globin chains and 2 Sigma-globin chains
(NOT found in adults)
Which chromosome are Beta-globin genes found on? what are the possible beta-like globins that are possible?
Chromosome 11 is where beta-like genes are found
Sigma, Gamma-g (glycine), Gamma-a(alanine), delta, or beta globin are all possible globins coded on chromosome 11
Which chromosome are Alpha-globin genes found on? what are the possible alpha-like globins that are possible?
Chromosome 16 is where all alpha-like genes are found
Zeta, alpha2, and alpha1 are all the possible globins at chromosome 16
Beginning with embryonic Hb, describe the order of hemoglobins that occurs until a year after birth.
until 8 weeks, Embryonic Hb is expressed (by the yolk sac)
Then HbF is made from the liver until 34-36 weeks gestation
HbA production starts after birth and reaches adult levels 1 year after birth
What type of anomaly occurs and at what AA position does it occur in order to cause sickle cell anemia? what is a current treatment for inducing HbF in pt’s with HbS?
HbS is caused by a substitution of Valine for Glutamic Acid at AA position #6
Hydroxyurea is being used to induce HbF in HbS pt’s, but it is a chemotherapeutic agent
Globin genes are arranged in ____ fashion and are ordered in the ___ __ ____ direction during embryonic, fetal, and adult development.
linear
5’ to 3’
True or False:
The heme group of hemoglobin is made of AA’s that allow a single Iron atom to attach to them. explain.
False
The heme group of hemoglobin is a prosthetic group (a non-AA group of a protein)
State 2 components of the heme group AND where it is located.
Heme is composed of an organic component (protoporphyrin) and a central Iron atom
It is nestled in a hydrophobic crevice of the protein chain
Define pyrrole. How many of these structures compose the heme group in hemoglobin?
Pyrrole: a ring structure composed of 4 carbon atoms and 1 Nitrogen atom
4 pyrrole rings form a tetrapyrrole that forms a single heme group
Describe the methyl groups, vinyl groups, side chains, and bonds of a heme group that attach to the iron atom in the center.
A single heme molecules has 4 methyl groups, 2 vinyl groups, and 2 propionate side chains
the iron atom lies in the center of the protoporphyrin and is bonded the the 4 pyrrole nitrogen atoms
How many helical segments are in a single hemoglobin subunit? how are they labeled?
8
A through H
Explain what it means when someone refers to the F8 histidine in a hemoglobin molecule.
It refers to the histidine that is the 8th AA residue in the F segment (6th segment) of hemoglobin
Name the proximal and distal histidines,why they are significant, AND which one donates a hydrogen bond
The proximal histidine is the F8 histidine
This binds to the heme group
The distal histidine is the E7 histidine
This histidine and O2 bind to the iron atom (between the heme and the E7 histidine) via a “hydrogen bond”
Describe the behavior of Hemoglobin upon binding to an O2 molecule
in deoxyhemoglobin, the iron atom of hemoglobin exists slightly outside of the plane of the porphyrin
Upon binding to O2, the F8 proximal histidine (which is attached to the globin chain) is pulled forward “0.4 A” and the iron moves into the plan of the porphyrin
This movement/conformational change makes hemoglobin have a higher affinity as EACH molecule of O2 is bound
Compare myoglobin to hemoglobin in terms of structure, function, number of heme groups, affinity for O2, and the genes that encode them
Myoglobin is an O2 storage protein that is common in muscles.
It is a monomer encoded by chromosomes 22 (not the globin genes)
Has 1 heme group, which has a high affinity for O2.
Hemoglobin is an O2 transport protein that is found in the bloodstream
It is a tetramers that is encoded by the globin genes (Chr. 11 and 16)
Has 4 heme groups with a lower “overall” affinity than myoglobin
True or False:
Both myoglobin and hemoglobin undergo a 0.4 A conformational change after binding to O2. explain
True
both hemoglobin and myoglobin do this, however it is relatively useless to myoglobin, while it greatly affects the binding ability of Hemoglobin
Compare the 2 oxygen dissociation curves for hemoglobin and myoglobin. include why they look the way they do.
Hb has a sigmoidal shape on it’s oxygen dissociation curve due to interactions between the globin unit’s as O2 binds and unbinds
Myoglobin has a hyperbolic curve on it’s oxygen dissociation curve due to it’s high affinity for O2
describe what pressure’s Hb and myoglobin bind to and dissociate from O2. What are their respective P50 values?
(P50 = the oxygen partial pressure at which a molecule is 1/2 saturated with O2)
Hb picks up O2 in the lungs around 100 mm Hg (100 Torr) and drops off O2 in tissues at 10 to 20 mm Hg (10-20 Torr)
Hb has a P50 value of 26 Torr
Myoglobin doesnt’y release O2 until pressure in tissues is very low (close to 0 Torr)
Myoglobin has a P50 value of 2.8 Torr
Explain what makes Hb even more efficient of an oxygen carrier during exercise.
when going from rest to exercising, there is a drop in O2 concentration from 40 Torr to 20 Torr.
This moves into the steepest part of the O2 dissociation Curve for Hb, which means Hb will be much more effective at transporting O2 (45% more effective)
Describe why the term “cooperativity” is applicable to the O2 binding behavior of hemoglobin. Also describe the reversibility of this concept.
each successive O2 molecule that is bound causes a conformational change that adjusts the other globin chains into a position where it becomes easier to bind to ANOTHER O2 molecule
(“it’s appetite for O2 grows as it gains O2”)
this also applies to the dissociation of O2 from hemoglobin in the tissues. As soon as one leaves, it is easier for the rest to leave as well.
What is 2,3-BPG and why is it important?
2,3-BPG is a product of metabolizing glucose and is therefore present in greater concentrations in highly metabolic tissues.
2,3-BPG reduces O2 affinity, which allows O2 to more easily dissociate from Hb molecules
Name a place in the body with low 2,3-BPG and a place with High 2,3-BPG.
There is no 2,3-BPG in the lungs
There is a lot of 2,3-BPG in the tissues (especially metabolically active ones)
Explain what exact type of interaction occurs between 2,3-BPG and Hb that reduces it’s affinity for O2.
2,3-BPG binds to the central pore of deoxyhemoglobin bin interacting with 3 + charged groups
This stabilizes the “T form” of Hb
Compare the state of the beta chains in a Hb molecule in the T form and in the R form. Which of these forms is predominant in smokers?
T form (non-oxygenated): beta chains are further apart (Smokers have a high population of their Hb molecules in the T form)
R form (oxygenated): beta chains are closer together
True or False:
pH does not have a significant effect on the affinity between Hb and O2. explain.
False
The binding affinity of Hb for O2 decreases as pH decreases (directly proportional)
Describe the pH of actively respiring tissues. What effect does this have on the conformation of Hb?
actively respiring tissues have a lower pH
lower pH means that there is more free H+, which binds to an AA and decreases the affinity of Hb for O2
Explain why HbF (fetal) has a higher affinity for O2 than the mother’s Hb. Why is this important?
HbF does not bind well to 2,3-BPG which means it maintains a higher affinity for O2 (it is locked in the R form) when in the presence of 2,3-BPG compared to the maternal Hb.
This is important so that the O2 can flow from the maternal Hb to the HbF and feed the fetus
Describe the “sequential model of cooperativity” in Hb
sequential model of cooperativity: at each level of oxygen loading, it causes an adjacent globin chain to change from the T form to the R form
True or False:
All Hb tetramers exist in either T state or R state. explain
True
Define Carboxyhemoglobin and why it can occur
Carboxyhemoglobin: when heme is combined with CO2
The bond between Hb and CO2 is much stronger than the bond it has with O2
(this can lead to death from overexposure to CO2)
What is HbA1c? what type of pt’s is this more prevalent in?
HbA1c: a post translational modification of the N-terminus of the Beta-globin chain of Hb (glycosylation or addition of glucose) that is irreversible
this form of Hb varies depending on the level of blood glucose concentration they have been exposed to in their 120 day lifespan
HbA1c is increased in diabetic pts and reflects how well they have been controlling their blood glucose levels for the last 120 days
State the 2 main types of hemoglobinopathies and BRIEFLY describe them
Sickle cell disease: is a structural issue that is caused by non-functioning globin protein
Thalassemias (2 types): is a quantitative issue that is caused by insufficient globin chains being produced
What is the most common monogenic disease in humans? what demographic does it occur at high frequencies in?
Thalassemias and they occur at high frequencies in mediterranean populations
The following are all symptoms of what condition?
Imbalanced globin-chain synthesis
Defective Hb production
Damage to RBC’s (or their precursors) from excess globin subunits
Thalassemia
Name all of the possible globin genes are deleted in a pt with alpha-Thalassemia.
Deletion of 1, 2, 3, or 4 alpha globin genes
Compare HbH and Hb Bart’s in terms of their globin chain abnormalities and the ages that they affect.
Hb Barts: occurs in fetal life and is caused by excess gamma globulin chains that form 4-gamma tetramers
HbH: occurs in adult life and is caused by excess beta-globin chains that form 4-beta tetramers
Both of these are due to alpha globin gene deletions that lead to the overexpression of whatever other globin is present
State the normal nomenclature for normal alpha genes. Also state the nomenclature for a single and then a double deletion of the alpha globin gene deletion.
alphaalpha
-alpha
–
Describe the following 4 types of classic alpha-thalassemias in terms of their genetic cause.
alpha+-thalassemia:
alpha-thalassemia:
HbH disease:
Hydrops fetalis with Hb Barts:
alpha+-thalassemia: 1 alpha gene got deleted (alpha-thalassemia silent carrier)
a silent hematologic phenotype or a moderate thalassemia-like hematologic picture
alpha-thalassemia: 2 alpha genes got deleted
HbH disease: 3 alpha genes got deleted
Hydrops fetalis with Hb Barts: both alpha genes are completely inactivated
What are the following symptoms consistent with?
Moderately severe anemia, microcytic, hypochromic hemolytic anemia, hepatosplenomegaly, and mild jaundice
Excess Beta chains form Beta4 tetramers (HbH) which precipitate to form inclusion bodies (Heinz bodies) which lead to hemolytic anemia
HbH disease (3 alpha genes got deleted)
What are the following symptoms consistent with?
Microcytosis (low MCV: mean cell volume), hypochromia (low MCH: mean cell Hemoglobin), and normal percentages of HbA2 and HbF
alpha-thalassemia (2 alpha genes got deleted)
What are the following symptoms consistent with?
gamma4 Hb is made (Hb Barts)
Hb Barts has a high O2 affinity so it takes O2 from the mother but cannot release O2 into fetal tissues = hypoxia and edema (hydrops) from CHF
stillborn or die a few hours after birth, exchange transfusion helps some, edema and severe hypochromic anemia occurs
Hydrops fetalis with Hb Barts (both alpha genes are completely inactivated)
What are the following symptoms consistent with?
a silent hematologic phenotype or a moderate thalassemia-like hematologic picture
alpha+-thalassemia: 1 alpha gene got deleted
alpha-thalassemia silent carrier
What is Cooley’s anemia? what causes it and describe the mechanism of disease
Beta-Thalassemia, which is caused by reduced beta chain synthesis due to beta globin gene issues
Excess alpha chains precipitate as inclusions and lead to profound anemia as they cause oxidative damage RBCs and their precursors
Compare the 2 main forms of Beta-thalassemia in terms of their genetic presentation and their symptoms
Thalassemia major form: has 2 defective beta-globin genes and cannot make any beta globin
leads to severe anemia
Thalassemia minor form: has only 1 defective beta-globin gene and can make 50% of the normal amount of beta-globin
leads to a more mild anemia
True or False:
The issue with alpha and beta thalassemias is that the beta and alpha chains respectively (the leftover globin in each disease) form tetramers and damage the RBCs of the pt, causing anemia. Explain.
False
Beta-Thalassemia leaves alpha-globins in the pt (some beta-globin is still present in the minor form), however alpha-globins CANNOT form tetramers.
Only beta-globins can form tetramers, so the damaging tetramers only occur in alpha-thalassemias.
HOWEVER, both alpha and beta thalassemias show the leftover globins precipitating and forming destructive inclusion bodies
True or False:
Beta-Thalassemia can affect transcription, RNA processing, or translation of Beta-globin RNA. Explain.
True
When is the initial presentation of beta-thalassemia first noted? explain why this occurs.
between 6-12 months of age (neonates) bc this is when the switch from HbF to HbA is supposed to occur.
However, beta-thalassemia pts cannot switch from gamma-globulins to beta globulins due to their defective beta-globin gene(s)
This causes a progressive drop in Hb levels as the pt’s Hb fails to switch to HbA and HbF cells die off
State 2 defining characteristics of beta-thalassemia that can be noted on a histological blood smear slide
teardrop cells and target cells
Describe the current treatment for beta-thalassemia pts and why it is an issue.
Transfusions have shown to treat beta-thalassemia, however it causes iron deposition in endocrine organs, liver, and heart
this leads to organ failure, more specifically, heart failure in the pt’s 20s to 30s
True or False:
HbF levels in a beta-thalassemia pt are the same as a normal healthy adult and this is not nearly enough to support the Hb needs of the pt. explain.
False
HbF is upregulated in beta-thalassemia pt’s, however it is not nearly quantitatively sufficient to meet the Hb needs of the pt.
so beta-thalassemia pt’s have more HbF than a normal person, however it is still not enough.
After a beta-thalassemia pt is already being treated with transfusions, name 3 routine efforts to improve the quality of life of the pt.
Iron chelation (removal of excess iron from the body) in an attempt to dampen the negative effects of the transfusions
Upregulation of HbF expression
Stem cell transplantation
