oxygen transporters Flashcards
myoglobin
the oxygen transporter for muscle
-monomeric
prosthetic group of hemoglobin and its location
- heme
- deep, nonpolar pocket which sequesters it from water and helps it to be in the +2 state
steric hinderance of carbon monoxide
-why this is important to myoglobin
- oxygen binds to heme at a 120 degree angle whereas carbon monoxide binds at a 90
- both oxygen and carbon monoxide must bind at 120 in myoglobin due to steric hinderance from a histidine residue
- this allows for oxygen to bind more readily to myoglobin than carbonmonoxide (which is a biproduct of heme degradation)
when oxygen binds to myoglobin…
the structure changes a little bit but since it is a monomer, this has little significance
hemoglobin
composed of an alpha and a beta subunits (2 of each)
- there is a heme in each subunit
- globular
- alpha and beta are nearly identical in sequence
Hill coefficient
-this defines the cooperativity of a molecule to its binding partner
->1 means positive cooperativity
-=1 no cooperativity
-
cooperativity of hemoglobin and myoglobin
- myoglobin shows no cooperativity since there is onle one heme (n=1)
- hemoglobin shows positive (n=2.8)
oxygen binding affinity of myoglobin and hemoglobin
- myoglobin has a much higher affinity since it needs to carry oxygen in the muscle where oxygen concentration is very low
- hemoglobin is more fit to deliver oxygen in other tissues throughout the body
T and R state of Hb
- stability
- contrast to myoglobin
- T state is deoxygentated, Hb has the lowest affinity to oxygen in this state. this is a more stable form because it contains more electrostatic and hydrogen bonds (taut)
- R state has an oxygen bound to heme, this triggers a conformational change in Hb. alpha subunit contacts the beta subunit, causing it take on the oxygen binding conf
- thesse forms differ in the arrangement of the subunits
- myoglobin is always set up to be a good oxygen acceptor
the bohr effect of Hb
- H+ and CO2 reduce the O2 affinity of Hb
- CO2 is in eq with carbonic acid and bicarb (pushes the dissociation curve to the right)
- this allows H+ and CO2 to allow Hb to deliver O to metabolically active tissues
haldane effect: deoxygenation of the blood increases its ability to carry carbon dioxide;
- deoxygenation of the blood increases its ability to carry carbon dioxide
- conversely, oxygenated blood has a reduced capacity for carbon dioxide
binding sites of O2, CO, H+, and CO2 on Hb
- O2 and CO bind to heme
- H+ and CO2 bind elsewhere on the protein and influence heme binding
BPG (DPG) binding to HbA
- binds to a pocket formed by the beta subunits
- lowers the affinity for O
- rises under low oxygen conditions allowing O to be deliveres efficiently
developmental regulation of Hb
-HbF and HbA
- composed of different subunits at different times in life
- HbF = 2 alpha, 2 gama
- HbA is 2 alpha, 2 beta
- these two are very simlar in sequence, structure and function
- except in their ability to bind another alosteric regulator (HbA for BPG)
- HbF binds oxygen with a higher affinity
affinity of HbF to O
- higher than HbA
- has fewer positive charges in its corresponding pocket
- HbF binds BPG less well and therefore binds oxygen with a higher affinity
histidines and Hb
- the proximal histidine forms a ligand to the iron which moves upon binding of O
- the distal histidine reduces CO binding
negative allosteric effectors
-CO2, H+, BPG
mutations in HbA
- some are nonpathogenic
- others, such as HbM or HbS, disrupt structure and function
Sickle cell anemia
- sickle appearence of RBCdue to insoluble HbS
- results in clogging of caps and organ dmage
- anemia, jaundice, frequent infections
- cna be homozygous (severe) or heterozygous (varies)
precipitating symptoms of sickle cell anemia
- reduced O levels during exercise can result in acute painful episodes due to the reduced O sickling the cells
- this is called a pain crisis caused by microvascular occlusion of bones
- treatment is hydration and pain control with NSAIDs
- provide oxygen to reduce sickling
mutation causing HbS
-subunit effected
- point mutation converting glutamate to valine on the exterior of the beta subunit
- can be diagnosed using electrophoresis as glutamate is very charged and val is neutral
mechanical mechanism of sickling sure to low O
- a hydrophobic hole it typically formed when there is no O in HbA
- however in HbS, there are hydrophobic knobs sticking out of the cell in the deoxy state
- alpah subunits are still normal in HbS
treatment of sickle cell
- antibiotic therapy: prevent secondary infection
- hydroxyurea: stimulates the production of HbF
- bone marrow transplant: replaces HbS with HbA
- gene therapy: worked in mice, current clinical trials
Methemoglobin (HbM)
- cause
- clinical manifestation
- diagnosis technique
- dietary cause
- acquisition
- this has an Fe3+ heme which can not carry oxygen
- presents with shortness of breath, cyanosis, and mental status change, head ache, fatigue, exercise intolerance
- methemoglobinemia is diagnosed by the absorbance spectrum of blood
- ingestion of nitrates and nitrites can promote HbM
- defects can also derive from a lack of reducing agents in the blood (vit C)
- can be in-born or aquired
thalassemias
- definition
- ethnical prev
- terminology
- treatment
- imbalance of the synthesis of the alpha and beta subunits of Hb
- prevelant in people of Mediterranean origin and some south asians have a carrier rate of 16%
- termed alpha and beta thalassemia depending on which subunits is lacking
- treatment usually involves transfusion
