Hemoglobin: Portrait of a Protein in Action

• To release O2 where the need is greatest. hemoglobin has evolved to respond to higher levels of these substance. H+ and CO2 are allosteric effectors of hemoglobin • The regulation of O2 binding by H+ and CO2 is call Bohr effect (1904) .7.3 H+ ions and CO2 Promote the Release of Oxygen: The Bohr Effect • Rapidly metabolizing tissues  general large amounts of H+ and CO2 .

4.2) At least two sets of chemical groups are important for sensing changes in pH: • α -amino groups of a chain N-term • side chains (His) of b146 and a122  pKa values near 7 .4)  77% (pH 7.The oxygen affinity of Hemoglobin↓ as pH ↓ (7. 100 torr)  Active muscle (pH 7.2): tendency to release oxygen increases For example: Transport The lungs (pH 7.2. 20 torr): Result: in a release of oxygen 66% (pH 7.4  7.

the terminal carboxylate group of β146 forms a salt bridge with α lysine residue in the α subunit of the other αβ dimer. Green dash line: hydrongen bond .• In deoxyhemoglobin. three amino acids form two salt bridges that stabilize the T state quaternary structure.  This interaction locks the side chain of histidine β146 in a position from which it can participate in a salt bridge with negatively charged aspartate β94 in the same chain • The formation of these salt bridges stabilizes the T state leading to a greater tendency for oxygen to be release. H-bond between protonated His β146 and β 94 Asp stabilize the salt bridge In deoxyhemoglobin.

high concentrate of CO2 leads to a drop in pH within red blood cell (RBC) Second. direct chemical interaction between CO2 and Hb stimulates oxygen release • carbonic anhydrase H2CO3: pKa 3.5 CO2 decrease the affinity of Hb for oxygen .CO2 stimulates oxygen release by two mechanisms First.

CO2 stabilizes deoxyHb by reacting with the terminal amino group to form carbamate group (.charged)  terminal amino group lie at the interface between the ab dimers  salt bridge stabilizes the T state (favoring the release of O2)  a mechanism of CO2 transport (~14%) .

A lesser amount is transport bay hemoglobin in the form of an attached carbamate .through antiporter Figure: transport of CO2 from tissues to lungs.and Cl. Most carbon dioxide is transported to the lungs in the form of HCO3.• CO2 released from RBC  lung (in the form of HCO3-) exchange of HCO3.produced in red blood cells and then release into the plasma.

4 Mutations in Gene Encoding Hb Subunits Can Result in Disease • The notion that: disease might be caused by molecular defects  Linus Pauling (1949)  to explain the blood disease sickle –cell anemia. • The name of the disorder the abnormal sickle shape of red blood cells deprived of oxygen .7.

• Sickle-cell anemia results form the aggregation of mutated deoxyHb molecules: Hb molecules have formed large fibrous aggregates • Figure: Sickle-cell hemoglobin fibers .

• Examination of the structure of hemoglobin S reveals that the new valine residue lies on the surface of the T-state molecule. decreased the solubility of deoxy Hb : Val6-Phe85. Lue88  aggregation HbS fiber is formed from 14 chains of multiple interlinked Hbs • Why do these aggregates not form when HbS is oxygenated? • : oxyHb in R state Phe 85. Leu88 on b chain are largely buried inside the Hb assembly .

Figure: Sickle-cell trait and malaria • A significant correlation is observed between regions with a high frequency of the HbS allele and regions with a high prevalence of malaria .

Thalassemia is caused by an imbalanced production of hemoglobin chains • Thalassemia. the order prevalent inherited disorder of hemoglobin . is caused by the loss or substantial reduction of a single hemoglobin chain.In β Thelassemia the β chain of hemoglobin is not produced in sufficient quantity .In α Thelassemia  the α chain of hemoglobin is not produced in sufficient quantity . . • Thelassemia is a set of related diseases.

The accumulation of free alpha-hemoglobin chain is prevented • AHSP: α -hemoglobin stabilizing protein. in RBCs • The ASHP binds to the α chain monomers and creates a highly soluble complex.Binds to the alpha chain as it is being produced -It is displaced when beta-hemoglobin is produced -Prevents accumulation of free alpha hemoglobin . does not precipitate AHSP: .It can bind to both the oxygenated and deoxygenated forms of the alpha chain .

Additional globin are encoded in the human genome In additional to the gene for myoglobin. Examination of the human genome sequence has revealed two additional globins: neuroglobin. and the one for β hemoglobin. cytoglobin . the two gens for α -hemoglobin. the human haploid genome contain other globin genes.

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decreases as temperature increases b. The amount of oxygen released by the hemoglobin molecules in the blood to the tissues…… a.Question 1. increases as pCO2 decreases B . decreases as pCO2 increases d. increases as blood pH decreases(acidity increases) c.

2. Most carbon dioxide is transported as __________ in the blood.  bicarbonate ions .

Which of these factors increases respiratory rate (increases release O2 )? A)increased blood pCO2 B)increased blood pH C)increased blood pO2 D)all of these A .3.

How does carbon dioxide form carbamate?  by reacting with the terminal amino group 6.4. What is the reason thalassemia occurs?  by an imbalanced production of hemoglobin chains . What do the three amino acids in deoxyhemoglobin form in order to stabilize the T state quaternary structure?  salt bridges 5.

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