10.08.18 Hemoglobin and Myoglobin Flashcards
Where does Hb bind O2?
Alveoli
How does Hb assist in maintaining acid-base balance in the body?
By binding CO2 from metabolism and releasing CO2 when Hb reaches the lungs
What is the bind O2/acid balance function of Hb dependent on?
partial pressure gradients of O2 or CO2
Synthesized inside muscle cells and stores oxygen there for use at times of high metabolic demand
Myoglobin
How does myoglobin content vary with skeletal muscle fiber type?
IA > IIA> IIB
- Single polypeptide chain
- 80% alpha helical
- closely packed tertiary structure
Single heme molecule covalently bound - Binds on O2 molecule at heme
Myoglobin
- 4 polypeptide chains (2 alpha, 2 beta)
- folds similar to myoglobin
- heme molecule covalently bound to each subunit- binds 4 O2
- Strong hydrophobic interaction between alpha and beta 1 and alpha and beta 2
- Weak polar interaction between a1b1 and a2b2
Hemoglobin
97-98.5% of total Hb in adults; glycosylation is marker for chronically elevated blood sugar
HbA (a2b2)
1.5-3% of total Hb in adult
HbA2 (a2delta2)
Fetal Hb, major Hb from ~1 month gestation until near birth; ~40% at birth
HbF (a2gamma2)
embryonic Hb, ~1 week post-conception until birth
HbE (zeta2epsilon2; a2e2; z2g2)
imbalance in globin chain synthesis; can be due to gene deletion, mutations that affect gene regulation or splicing
Thalassemias
What gene is dysregulated for beta-thalassemia minor
1 beta
what gene is dysregulated for beta-thalassemia major (excess alpha chains, do not form tetramer)
2 betas
what gene deletion usually has no symptoms?
1 alpha
what gene deletion results in alpha-thalassemia trait
2 alphas
What gene deletion results in HbH disease (names after beta4 tetramer formed here)
3 alphas
What gene deletion results in Hb Bart’s disease or hydrops fetalis (Hb Bart’s is gamma4 tetramer)
4 alphas
Fe-protoporphyrin IX
heme
rings that form coordinate covalent bonds to Fe2+
Pyrrole rings
the chains from the pyrrole rings interact with the surrounding alpha/beta globin chains to stabilize heme binding
hydrophobic
What color is cyanocobalamin (Vit B12)
Pink
mutations of the heme biosynthesis pathway
Porphyrias
binding curve is hyperbolic, indicating a single constant affinity for O2
binding curve is sigmoidal, indicating changing affinity for O2 over the binding curve
Myoglobin
Hemoglobin
partial pressure of O2 at which 50% of O2 binding sites are occupied
P50
What does the taut conformation favor and what does the relaxed conformation favor?
Deoxy- T
Oxy- R
Produced in RBCs when glucose is abundant; binding allows Hb-bound O2 to dissociate and to supply O2 to tissues operating at a high metabolic rate; makes O2 release and is responsive to hypoxia allowing release at low pO2
2,3 DPG
What physiological changes causes 2,3 DPG levels to change?
- Chronic Obstructive Pumonary Emphysema
- High Altitude
- Chronic Anemia
- Pregnancy
In the lungs, high PO2 drives binding of O2 to Hb, release of H+ and formation of H2CO3. CA equilibrium favors synth of CO2 and H2O
Haldane effect
In RBCs, protons bind to Hb and favor the T state, favoring O2 release
Bohr effect
How does increase/decrease in pH affect O2 binding?
Increase favors O2 binding
Decrease favors O2 release
has a different beta chain and has a higher affinity for oxygen than adult hemoglobin; binds 2,3 DPG poorly
HbF
Most common Hb variant
beta s variant
What is the mutation in the beta s variant?
Glu6 changes to Val6
What does HbA competitively bind to and why do they inhibit oxygen binding?
- Cyanide
- Carbon monoxide
- Nitrogen dioxide
- Hydrogen sulfide
Don’t change oxidation status of iron from Fe2+ to Fe3+ (results in O2 release)
Mutations in any of the 3 AA on the distal side of the heme; characterized by cyanosis and brown color to blood
Hereditary Methemoglobinemia
What are some other causes of methemoglobinema?
- Mutations in PPP (G6PDH deficiency) because glytathione normally reduces ROS and prevents methemoglobin formation
- Mutation in cytochrome b5 reductase (uses NADH from glycolysis to reduce Fe3+ in methemoglobin to Fe2+ and reversing formation of Fe3+)