MCP Flashcards
basic structure of myoglobin and hemoglobin
myoglobin: primary structure= 153 AA intracellular protein, secondary structure= 8 alpha-helices with a heme prosthetic group in a hydrophobic pocket, tertiary structure: similar to alpha and beta Hb subunits only longer
hemoglobin: globular tetrameric protein with the quaternary structure of a2b2 (dimer of ab protomers) arranged as a tetrahedron where each chain is bound to a heme (thus binds 4 O2 molecules= 8 oxygen atoms) and the two ab dimers switch back and forth between states T and R (15 degree rotation)
- ApoHb: a2b2 without prosthetic groups
- HoloHb: ApoHb + 4 hemes
cooperative O2 binding
reflects the existence of two Hb states (T and R) in which the more O2 bound to a tetramer, the greater the affinity is for binding another oxygen (what is happening at one site promotes the same things happening at another identical site- requires having multiple sites of the same kind)
T- low affinity
R- high affinity
(when equilibrium is affected by something other than oxygen, the steep region of the sigmoidal Hb oxygen dissociation curve shifts to the left or right)
the effect of pH, [CO2] and [BPG] on the O2 binding curve
pH= higher pH- O2 is loaded; lower pH- O2 is released
[CO2]= high CO2 lowers pH releasing O2; low CO2 increases pH loading O2
[BPG]= moves curve to right, stabilizing the T-state
sickle cell anemia
HbS occurs when there is a single substitution (Glu–>Val) at the beta 6 position leading to hemolytic anemia if individuals are homozygous for the gene causing aggregation and polymerization into rigid extended helical fibers and distortion of the RBC shape into sickles)
if heterozygous, Hb is 40% of its normal value leading to a shorter than normal lifetime for erythrocytes but a 73% reduced rate of contracting malaria (evolutionary selected protection)
thalassemia and possible treatments
insufficiency of alpha or beta chains leading to insufficient or non-functional hemoglobin. major= lack of chains (homozygous or compound heterozygous) and minor= decreased chains (simple heterozygous-carrier)
alpha-thalassemia: defect in alpha chain production; b4 or g4 (HbH in adults and HbBarts in fetuses)
beta-thalassemia: defect in beta chain production
*treatments: blood transfusion (temporary) or bone marrow transplant
methemoglobinemia
hemoglobin in which the heme iron has been oxidized to the ferric state preventing the binding or release of O2 caused by mutations that may stabilize the oxidized form, CYB5R defect or chemical agents such as nitrite
adaptive mechanisms to make up for insufficient diffusion
oxygen carriers (respiratory pigments: hemoglobin and myoglobin) and circulatory systems (respiratory fluid: blood) to speed up downhill diffusion from alveoli (100 torr) to capillaries in active tissues (20 torr)
*myoglobin: facilitates O2 diffusion to the mitochondrion within the muscle cell
protomer
the smallest subassembly with the same composition as the whole complex
example: ab in Hb (which is a2b2)
heme structure
Fe chelated by protoporphyrin IX- which is a porphyrin (tetrapyrrole bridged by methylene groups) attached to 4 methyl, 2 vinyl and 2 propionate substituent groups
Fe binds O2 and is hexacoordinate with 4 equatorial ligands bound to 4 nitrogen atoms facing the center of the structure and 2 axial ligands in front and behind of the heme plate
deoxy vs. oxyHb structure
deoxy: iron is pentacoordinate instead of hexacoordinate since there is an empty space on the distal side of the Fe (“distal heme pocket”) which is where O2 usually binds
oxy: Fe is hexacoordinate in which the O2 is bound between the Fe (II) and His E7 (distal His), through hydrogen bonding, which destabilizes an intermediate formed when O2 tries to oxidize Fe and lowers the affinity for CO
* has 5 nitrogens- 4 from pyrroles and 1 from the proximal His side chain
colors of blood when Hb is oxygenated or deoxygenated and when Hb and Mb is oxidized
ferro/Fe (II)/ferrous:
1. oxyHb: (O2 is present) brilliant scarlet (transmits more light in red region)
- deoxyHb: (no O2) dark red
ferri/Fe (III)/ferric:
1. oxidized Hb/Mb: yields metHb/metMb which is brown-red like dead meat
poisons that bind as the 6th ligand
Co, NO, H2S, and anions cyanide, azide, and sulfide (CN-, S-) bind as the 6th ligand and prevent O2 from binding making them toxic
oxygen dissociation curves for Mb and Hb
Mb: hyperbolic curve with a low P50 (2.6 torr) and binds O2 under conditions in which Hb releases it
Hb: sigmoidal curve with a high P50 (26 torr)
allostery
an effect of the same or different molecule binding at another site that is different
positive and negative effectors of Hb oxygen dissociation curve
positive effector: increases affinity (O2) shifting curve to the left thus stabilizes the R state
negative effector: decreases affinity and shifts the curve to the right thus stabilizing the T state
*increases the affinity for O2 in the lungs to promote full saturation and decreases the affinity in the tissues to promote unloading
BPG
negative effector that adjusts the overall average P50 to put the steepest part of the binding curve between the lung pO2 and the tissue pO2 changing midpoint affinity stabilizing the T state by cross-linking the b subunits thus decreases Hb’s oxygen affinity allowing it to be released (efficient O2 carrier)
*responds to long-term changes
