Lecture 6: Hemoglobin Flashcards
Porphyrin
Heme-containing protein
Heme prosthetic group
Planar porphyrin ring with ferrous (Fe2+) ion in center ring
Hemoglobin vs myoglobin
Myoglobin: heme-containing monomer with hyperbolic O2 curve that stores oxygen in muscle.
Hemoglobin: heme-containing tetramer with sigmoidal O2 curve that transports oxygen in RBCs.
HbA structure
Tetramer with 2 alpha chains and 2 beta chains (2 alpha-beta dimers). Transports 4x O2
HbF structure
Tetramer with 2 alpha chains and 2 gamma chains (instead of beta)
Hb T and R states
Taut (T) = deoxyHb form
Relaxed (R) = oxyHb form
How does oxygen binding affect the structure of hemoglobin?
O2 binding pulls the Fe2+ more into the heme ring plane. This movement ruptures some of the polar bonds between the Hb dimers and makes further O2 bonding more stable
Hb vs Mb oxygen binding curves
Mb has a hyperbolic curve and is always higher affinity vs Hb. Hb’s sigmoidal curve reflects cooperative binding behavior.
Under what allosteric conditions is T Hb most stable?
Taut Hb (low O2 affinity) is stabilized by low pH, low pO2, high pCO2, and high 2,3-BPG concentrations. Opposite stabilizes R Hb
Bohr effect
Release of oxygen by Hb is enhanced by low pH and high pCO2. High CO2 also creates more bicarb + H+, lowering pH even more.
Why is allosteric regulation of Hb useful?
Metabolically active tissues produce 2,3-BPG, CO2, and H+ and demand more oxygen. Allosteric regulation of Hb O2 affinity supports rapid oxygen unloading/delivery in areas that need it most.
What is HbF’s O2 dissociation curve like?
HbF also has a sigmoidal O2 curve, but is slightly left-shifted compared to HbA. Higher O2 affinity enables HbF to take oxygen from HbA across the placenta
Thalassemia
Loss of or reduction in production of alpha or beta chain. Results in low levels of functional Hb and more RBC turnover.
When does fetal hemoglobin go away?
Fetal hemoglobin persists at high levels until around 6 months post-natal.
Sickle cell disease
Caused by Glu->Val at position 6 on beta chain. Deforms RBC into inflexible sickle shape. Blocks microvessels, causes local anoxia/lactic acid build up, self-associates other RBCs to sickle, causes vaso-occlusive crises.
HbC disease
Glu->Lys at position 6 on beta chain. Mild, chronic hemolytic anemia
Degrees of severity of alpha-thalassemia
1 deletion = silent carrier
2 deletions = minor
3 deletions = HbH disease
4 deletions = Hb Bart; fatal hypoxia by neonatal age
HbH disease
Form of alpha-thalassemia where beta-4 Hb tetramers (HbH) bind O2 with high affinity and no cooperativity. RBCs precipitate out over time.
HbE disease
Form of beta-thalassemia with a single point mutation in the beta chain. Alpha-4 tetramers lack cooperativity and are insoluble
Degrees of severity of beta-thalassemia
Beta-thalassemia minor: 1 of 2 beta genes is mutated, mild.
Beta-thalassemia major: no functional beta genes. Also Mediterranean/Cooley’s anemia. Abnormal growth, development, and bone formation (chipmunk face) and iron deposition on organs due to transfusions/RBC turnover.
Hemoglobin A1c
Hb A1c is irreversibly glycated Hb. Normally 4-6% of adult Hb, extent depends on blood glucose. Serves as indicator for average blood glucose over time.
Methemoglobinemia
Oxidation of ferrous (Fe2+) to ferric iron (Fe3+) in heme. Results in high O2 affinity + no O2 delivery. Normally <1%, levels >50-60% fatal.
Maintenance of methemoglobin
- H2O2 cleared by reduced glutathione (GSH)
- NADH/NADPH reduce MetHb via Methemoglobin Reductase enzyme.
Congenital methemoglobinemia
Caused by globin mutations stabilize ferric iron and make it more resistant to reduction by MR. Alternatively, mutations in enzymes that reduce metHb to Hb.
Acquired methemoglobinemia
Caused by use/exposure to oxidizing drugs, chemicals, or toxins. Increased metHb production overwhelms physiological reduction mechanisms.
