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the oxygen transporter for muscle


prosthetic group of hemoglobin and its location

-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



composed of an alpha and a beta subunits (2 of each)
-there is a heme in each subunit
-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
-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)
-clinical manifestation
-diagnosis technique
-dietary cause

-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


-ethnical prev

-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