- Hemoglobins are mutated in that they have less affinity for oxygen and are degraded by erythrocytes (red blood cells) 
- Causes a decrease in the red blood cell count and thus decrease oxygen flow to the tissues.


Hemolytic anemia

- Mutations of the oxygen binding site of hemoglobin causing oxidation of Iron II to Iron III 
- The cooperativity of the binding pockets are decreased in hemoglobin. 
- People exhibit a bluish skin because this mutation creates methemoglobin. 


Cyanosis 

- Mutations found to increase oxygen affinity to the hemoglobin.
- This causes increased amounts of red blood cells to compensate for less oxygen being released to the tissues. 

Polycythemia 

- Inheritable blood disease 
- Homozygous (or those with both genes) people with hemoglobin S have sickle-cell disease. 
- Heterozygous individuals usually live healthy lives but have lower erythrocyte count.
- The cells form a sickle shape because of one amino acid is mutated (Glu -> Val)
- This amino acid change allows the hemoglobin to bind to other hemoglobin at the binding pocket causing a mass sickle shape of the blood cells. 
- It is difficult for cells to pass through capillaries and deliver oxygen which can cause tissue death. 


Sickle-cell anemia

There are many diseases associated with mutations in hemoglobin.
- Sickle-cell anemia 
- Polycythemia 
- Cyanosis
- Hemolytic anemia

Grand Valley State University

- Tetramer of myoglobin-like polypeptides (dimer of alpha beta subunits)
- Delivers oxygen to tissues throughout the body.
- Once oxygen binds, structural change causes oxygen binding affinity to grow in the three other binding sites
- Hemoglobin has two conformation states:
  - T-state
  - R-state


Hemoglobin

Voet, D., Voet, J. G., & Pratt, C. W. (2013). Chapter 7: Protein Function: Myoglobin and Hemoglobin, Muscle Contractions, and Antibodies. In Fundamentals of biochemistry: Life at the molecular level (4th ed., pp. 176-216). Hoboken, NJ: Wiley. Retrieved February 21, 2021, from archive.org.

Fundamental of biochemistry: Life of the molecular level 4th edition: Chapter 7

- A flat ring that contains an iron atom in the center that binds the oxygen atom in a reversible reaction to be able to release oxygen.
- The heme group binds to myoglobin 
- Heme binds four times to hemoglobin 
- Oxygenation of heme causes hemoglobin to change color from dark purple to a scarlet color. 
- In addition to oxygen, however, it can bind things like NO, CO, and H2S and they bind to a higher affinity than oxygen which is evidence of the toxicity of CO.
- CO has a 200-fold greater affinity for hemoglobin than oxygen. 

Heme

- The hemoglobin curve has a sigmoidal (S-shaped) curve instead of the hyperbolic curve for myoglobin.
- Cooperative interaction between the binding sites is displayed, because once a single oxygen binds to hemoglobin the affinity for oxygen at the other sites increases affinity for oxygen at the other subunits. 
- As more oxygen atoms bind to hemoglobin, the slope of the curve increases. 
- Hemoglobin is more saturated with oxygen in arterial oxygen pressures and in venous oxygen pressures hemoglobin is only about half saturated with oxygen. 
- Additionally, the background indicates the color change that occurs with oxygen binding to hemoglobin (blue to red). 


Hemoglobin binding curve

Mutations in hemoglobin

- There are additional compounds in the blood stream that effect the oxygen levels besides CO2
- The compound 2,3-bisphosphoglycerate (BPG) binds to deoxyhemoglobin (empty O2 bound hemoglobin) 
- BPG in blood decreases the oxygen affinity by keeping hemoglobin in the deoxyhemoglobin conformation. 
- In the absence of BPG, O2 would not release from the hemoglobin.

2,3-bisphosphoglycerate (BPG)

-  The T-state is the hemoglobin conformational state of deoxyhemoglobin, or the hemoglobin without oxygen bound.
- The iron is situated 6 Angstroms out of the heme and allows for the iron to access oxygen. 


T-State of Hemoglobin

- R-state is the conformational state of oxyhemoglobin.
- When oxygen binds, it “flattens” the iron complex. 
- To prevent steric clash during flattening of the heme, there is an alpha helix that tilts as well.
- Overall, changes in hemoglobin's conformational states at the tertiary level cannot occur without causing quaternary structure changes in the whole protein. 

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