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Protien Metabolism
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Protien Metabolism

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  • 1. Protein Function Structure will determine the function of the protein www.freelivedoctor.com
  • 2. Key ideas and terms
    • protein can bind a ligand in the binding site
    • For an enzyme, the ligand is a substrate and they bind in what is called the active site
    • ligand has to be the correct shape
    • ligand has to have the complementary charges and hydrophobicity or hydrophilicity
    www.freelivedoctor.com
  • 3. Lock and Key Hypothesis
    • Protein and ligand have complementary shapes.
    • Interactions must also be complementary
      • If enzyme charge is negative, substrate must be positive
      • If pocket is nonpolar, ligand must be nonpolar
    • Antibodies
    www.freelivedoctor.com
  • 4. Induced Fit
    • Induced Fit: when the protein and ligand bind, the protein may change conformation to allow for tighter binding
    • Frequently, both the ligand and the protein change conformation
    www.freelivedoctor.com
  • 5. Examples: O 2 binding proteins: myoglobin and hemoglobin
    • oxygen is not water soluble yet needs to be transported
    • diffusion is not effective
    • myoglobin is found primarily in muscle tissue
    • Hemoglobin is in the blood
    • Both proteins contain heme
    www.freelivedoctor.com
  • 6. Heme Group
    • consists of a Fe 2+ and a protoporphyrin ring to help stabilize the iron(II) ion
    www.freelivedoctor.com
  • 7. Heme Group
    • the iron must be a 2+ to bind oxygen. The heme group is buried deep within the protein so that the iron is not oxidized to 3+
    • there must be flexibility in the protein to allow for oxygen to attach and then let go
    • Iron has 6 coordination sites.
      • Four of them used by porphyrin. Unshared pairs on nitrogen complex to iron
      • Fifth and 6 th for oxygen and protein
    • Heme is planar
    www.freelivedoctor.com
  • 8. Myoglobin
    • has heme group
    • eight alpha helical segments
    • dense hydrophobic core
      • all but two polar groups on outside
      • room for only 4 water molecules
    • flat heme in pocket
    • iron coordinated to poryphorin and H
    • As well as the heme
    www.freelivedoctor.com
  • 9. Myoglobin Binding Curve
    • Hyperbolic binding curve
    • Relatively insensitive to small changes in oxygen concentration
    www.freelivedoctor.com
  • 10. Myoglobin
    • The P50 (oxygen partial pressure required for half saturation) for myoglobin is very low
    • Myoglobin has a high affinity for oxygen-an important characteristic for a protein that must extract oxygen from the small amounts present in blood.
    • At the oxygen concentration existing in the capillaries, the myoglobin in adjacent tissues is nearly saturated.
    • When cells are metabolically active, their internal P O2 falls to levels where myoglobin will lose (deliver) its oxygen .
    www.freelivedoctor.com
  • 11. Hemoglobin
    • Quaternary structure : 4 subunits
    • Each subunits is like myoglobin
    • Each subunit has heme group
    • 2 alpha chains; 2 beta chains
    • Few contacts between alpha and betas, more between alphas and betas
    www.freelivedoctor.com
  • 12. Hemoglobin
    • Exists in two states
      • R state (high affinity for O 2 )
      • Where would this state be favored?
        • In the lungs
      • T state (low affinity for O 2 ) (deoxyhemoglobin)
      • Where would this state be favored?
        • In the tissue
      • Sensitive to pressure changes
      • On oxygenation, one pair of subunits shifts with respect to the other by a rotation of 15 degrees.
    www.freelivedoctor.com
  • 13. Hemoglobin
    • deoxy hemoglobin (T) oxy hemoglobin (R)
    www.freelivedoctor.com
  • 14. Oxygen Binding to Heme in Hemoglobin
    • Fe is coordinated to a histidine in helix 8 of the Hb molecule
    • In deoxy form, porphyrin is puckered and Fe is out of the plane of the heme
    • When oxygen binds the Fe (at other coordination site) the Fe is pulled into the plane of the heme
    • This pulls on the histidine, which pulls on the helix, changing the shape of the molecule.
    Fe 2+ His F8 0.6 A O 2 www.freelivedoctor.com
  • 15. Hemoglobin
    • Conformational changes in hemoglobin alter its binding ability
    • Binding of oxygen in one subunit causes conformational changes in the next subunit
    • This is called cooperative binding
    • This can happen because it is composed of 4 independent subunits
    • produces a different binding curve that is sigmoidal
    • The modulation of the affinity of a site for a ligand by ligand binding at another site is called Allostery .
    www.freelivedoctor.com
  • 16. Hemoglobin Binding Curve www.freelivedoctor.com
  • 17. Bohr Effect
    • Hemoglobin's affinity for oxygen is decreased in the presence of carbon dioxide and at lower pH.
    • Carbon dioxide reacts with water to give bicarbonate, carbonic acid free protons via the reaction:
      • CO 2 + H 2 O ---> H 2 CO 3 ---> H + + HCO 3 -
    • Protons bind at various places along the protein and carbon dioxide binds at the alpha-amino group forming carbamate.
    • This causes a conformational change in the protein and facilitates the release of oxygen.
    www.freelivedoctor.com
  • 18. Bohr Effect
    • Blood with high carbon dioxide levels is also lower in pH (more acidic). (recall the equilibrium)
    • Conversely, when the carbon dioxide levels in the blood decrease (i.e. around the lungs), carbon dioxide is released, increasing the oxygen affinity of the protein.
    www.freelivedoctor.com
  • 19. Bohr Effect Summary
    • High CO 2 in tissues
    • Higher H+
    • Lower pH
    • Affinity for O 2 decreases
    • O 2 released to tissues
    • T state favored
    • Low CO 2 in lungs
    • Lower H+
    • Higher pH
    • Affinity for O 2 increases
    • O 2 binds hemoglobin
    • R state favored
    www.freelivedoctor.com
  • 20. Hemoglobin and CO poisoning
    • Other ligands can compete with oxygen for binding to hemoglobin
    • The binding of oxygen is affected by molecules such as carbon monoxide (CO) (For example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site.
    • Hemoglobin binding affinity for CO is 200 times greater than its affinity for oxygen, meaning that small amount of CO can dramatically reduces hemoglobin’s ability to transport oxygen.
    • Hemoglobin also has competitive binding affinity for Nitrogen Dioxide and Hydrogen sulfide .
    www.freelivedoctor.com
  • 21. Oxygen and Carbon Monoxide
    • Oxygen and carbon monoxide same size and shape.
    • Carbon monoxide, however has formal charge
    • Sticks to Fe better
    • Blocks oxygen binding
    www.freelivedoctor.com
  • 22. Hemoglobin and 2,3 DPG
    • In people acclimated to high altitudes, the concentration of 2,3-diphosphoglycerate (2,3-DPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension.
    • This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect .
    www.freelivedoctor.com
  • 23. Sickle Cell Anemia
    • Sickle cell disease is caused by an abnormal adult hemoglobin, called hemoglobin S. People with sickle cell disease make hemoglobin S instead of hemoglobin A.
    • Single amino acid substitution
      • glutamate changed to valine
    • To show condition, have to have mutation in both genes (Homozygous)
    www.freelivedoctor.com
  • 24. Sickle vs normal hemoglobin
    • first 9 amino acids of normal hemoglobin beta chain
      • v h l t p e e k s
    • first 9 amino acids of sickle hemoglobin beta chain
      • v h l t p v e k s
      • Notice the single amino acid change?
    www.freelivedoctor.com
  • 25. Sickle Cell Anemia
    • Position 6 is on outside of molecule
    • Glutamate is polar
    • Valine substitution causes “sticky spot” on outside of hemoglobin
    • Causes hemoglobin molecules to stick together
    • Forms long chains which cause red blood cell to sickle
    www.freelivedoctor.com

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