Structure & Function of Hb/Mb Flashcards
Where does Hb bind and release O2, respectively?
Lungs (alveoli) & Tissues
Where does external respiration (exchange of gas with external environment) occur?
alveoli of the lungs
Where does internal respiration (exchange of gas with internal environment) occur?
Tissues
What drives the exchange of gases (O2 & CO2) across the membranes?
Partial pressure (pressure gradient)
Characteristics of Myoglobin
tertiary structure of a single polypeptide chain; most are in alpha-helical shape; 1 O2 at heme; O2 storage in tissues;
NOT allosteric (only those with quaternary structure can be allosteric)
Characteristics of Hemoglobin
Tetramer of 4 polypeptide chains (2 alpha & 2 beta chains); 4 O2 per Hb; O2 transport from lungs to tissues; CO2 from tissues to lungs; allosteric protein (since it has quaternary structure)
HbA is composed of
a2B2
most abundant (98%) type of normal Hb in adults
HbA2 is composed of
a2D2
rest type (2%) of normal Hb in adults
HbF is composed of
a2Y2
major Hb in fetus until birth
HbE is composed of
S2E2 or a2E2 or S2Y2
Embryonic Hb until birth
What is the disorder caused by mutations in gene that is responsible for globin chain synthesis?
Thalassemia
Structure of Heme
Fe-protoporphyrin IX
- one Fe2+ molecule is covalently bonded to 4 pyrrole rings.
- hydrophobic chains formed by the pyrrole rings stabilize heme binding.
What gives heme its red pigment?
porphyrin rings
what other colors are given by porphyrin rings?
chlorophyll (green)
cyanocobalamin or B 12 (pink)
What is the disorder caused by mutations in the heme biosynthesis pathway?
porphyria
Binding curve of Mb
Hyperbolic; binds O2 tightly at all times; only releases O2 when under stress conditions
Binding Curve for Hb
Sigmoidal; lower affinity for O2 than Mb; releases 50% of O2 in tissues
T state of Hb
Tense; in tissues; low O2 affinity; Deoxyhemoglobin
R state of Hb
Relaxed; lungs (R=respiratory); high O2 affinity; Oxyhemoglobin; binding of O2 stabilizes R state due to positive cooperativity
T/F: O2 is a positive allosteric regulator of Hb O2 binding because O2 causes a conformational change at each aB dimer interface in the Hb molecule.
True
Negative Allosteric Inhibitors
Stabilize T state; negative effect on O2 binding=release of O2; shifts curve to right; 2,3-BPG, CO2, H+ (decrease pH-Bohr Effect)
2,3- BPG
Negative Inhibitor; binds central cavity and holds Hb in T state
What are situations in which 2,3-DPG levels are increased?
- COPD
- Pregnancy
- High altitude
- Chronic Anemia
CO2
Negative Inhibitor; binds N-terminus creating a negative charge, allowing ionic binds to stabilize the T State
Haldane Effect
The Haldane effect describes how oxygen concentrations determine hemoglobin’s affinity for carbon dioxide.
For example, high oxygen concentrations enhance the unloading of carbon dioxide.
Bohr Effect
The Bohr effect describes how carbon dioxide and H+ affect the affinity of hemoglobin for oxygen.
High CO2 and H+ concentrations cause decreases in affinity for oxygen, while low concentrations cause high affinity for oxygen.
What reaction is carried out by Carbonic Anhydrase?
- CO2 + H2O –> H2CO3
2. H2CO3 –> CO2 + H2O
H+
Negative Inhibitor; Decreases pH; Bohr Effect: high H+ in cells causing release of O2; low H+ in lungs allowing binding of O2
Differences of Hb A and Hb F
- Hb F has Y chain instead of B chain
- Hb F > Hb A for oxygen affinity
- Hb F binds 2,3-DPG poorly
Oxygen released by maternal Hb A is bound by Hb F and transported to fetal tissues.
The most common Hb variant (mutation) associated with pathology in the U.S. is
Bs variant
- Bs mutation can lead to increased production of Hb S which is responsible for sickle cell disease.
What are substances that compete with oxygen for binding at heme and inhibit oxygen binding?
CN- (cyanide); CO (carbon monoxide); NO2 (nitrogen dioxide); H2S (hydrogen sulfide)
They don’t change Iron oxidation state
Carboxyhemoglobin
Complex formed of CO and heme that is readily formed and more stable than oxyhemoglobin (HbO2).
Elevated level of carboxyhemoglobin can lead to CO poisoning
What is the disorder caused by mutations in any of 3 AAs on the distal side of heme?
Methemoglobinemia
Due to oxidation of Fe2+ to Fe3+ and is characterized by cyanosis (brown color of blood)
What are other causes of methemoglobinemia?
- Decrease in glutathione caused by mutations in the PPP causing G-6-PD deficiency.
- Mutations in cytochrome b5 reductase causing inability of Fe3+ reduction to Fe2+ in methemoglobin.