Metabolism of Oxygen Binding Protein

• Heme proteins

  • Specialized proteins containing heme as a prosthetic group
  • Hemoglobin and myoglobin are the two most important heme-proteins in humans
  • Heme group binds oxygen reversibly
  • Tetrameric hemoglobin molecule is structurally and functionally more complex than myoglobin
• Synthesis of Hemoglobin

  1. Heme and globin produced at two different sites in the cells: Heme in mitochondria, Globin in polyribosomes

  2. Heme consists of a porphyrin ring system with an Fe+2(ferrous) fixed in the center through complexation to the nitrogens of four pyrrole rings

  3. Protoporphyrin consists of 4 pyrrole rings
• Iron

  • Has 6 coordination, 4 bind with the four pyrrole rings of protoporphyrin
  • 1 bind with histidine (amino acid) from globulin
  • 1 bind is free (bind to oxygen, CO2 respectively)
  • The reduced state is called ferrous (Fe+2) and the oxidized state is called ferric (Fe+3)
  • Iron remains in the ferrous state (Fe+2) in hemoglobin
• Hemoglobin

  • Responsible for transporting oxygen
  • Structure: 4 heme + 4 globin
  • Globin: Four globin chains (2 alpha and 2 Beta)
  • Heme: Porphyrin ring with central iron
  • Iron: Site of attachment with O2 (Oxy-Hb and Deoxy-Hb)
• Structure of Hemoglobin

  • Primary structure made up of amino acids
  • Secondary structure is alpha helix and each globin contains eight alpha helices
  • Tertiary structure describes how each globin bends in space
  • Quaternary structure is these units fitting together
• Types of Hemoglobin

  • Embryonic hemoglobins
  • Fetal hemoglobin
  • Adult hemoglobins
• Embryonic Hemoglobins

  • Hb Gower I (zeta2epsilon2)
  • Hb Portland (zeta2gamma2)
  • Hb Gower II (alpha2epsilon2)
• Fetal Hemoglobin

  • HbF (alpha2gamma2)
• Adult Hemoglobins

  • Hb A (alpha2beta2)
  • Hb A2 (alpha2delta2)
  • Hb F (alpha2gamma2)
• The normal adult hemoglobin molecule contains two alpha-globulin chains and two beta-globulin chains
• In fetus and infant, the hemoglobin molecule is made up of two alpha chains and two gamma chains
• As the infant grows, the gamma chains are gradually replaced by beta chains, forming the adult hemoglobin structure
• Secondary Structure of Hemoglobin


  • Similar secondary structures of α- and β-chains
  • Each chain contains helical and nonhelical segments surrounding a heme group
  • Eight helices area from A to H
  • Heme lies in a hydrophobic crevice between helices E and F
• Heme lies in the cleft between helices E and F
• In oxy-Hb


  The 6th valency of iron binds the O2. The oxygen directly binds to iron and forms a hydrogen bond with an imidazole in alpha chain nitrogen of the distal histidine
• In deoxy-Hb

  A water molecule is present between the iron and distal histidine
• Hemoglobin has two quaternary structures
• 1. state is the deoxy form of hemoglobin, also called the "T" form or taut or tense form. It is the low oxygen affinity form of Hemoglobin
• 1. state is the oxy form, the binding of hemoglobin causes rupture of some of the ionic bonds and hydrogen bonds between the αβ dimers
• When in a tense form, Hb is not oxygenated, 2,3-DPG is at the center of the molecule, and the salt bridges between the globin chains are in place
• When oxygenated, the relaxed form is in place; 2,3-DPG is expelled, salt bridges are broken, and the molecule is capable of fully loading oxygen
• The R form is the high oxygen affinity form of hemoglobin
• The primary function of hemoglobin is to transport oxygen from the lungs to the tissues
• Hemoglobin forms a dissociable complex with oxygen: Deoxyhemoglobin + 4O2 = Oxyhemoglobin
• The binding and release of oxygen from the hemoglobin molecule are defined by the oxygen dissociation curve (OD curve) represented as a sigmoid shape
• The sigmoidal oxygen dissociation curve reflects specific structural changes that are initiated at one heme group and transmitted to other heme groups in the hemoglobin tetramer
• The affinity of hemoglobin for the last oxygen bound is approximately 300 times greater than its affinity for the first oxygen bound, known as heme-heme interaction
• Left shift indicates higher O2 affinity, while right shift indicates lower O2 affinity
• The causes of shift to the right can be remembered using "CADET" for CO2, Acid, 2,3-DPG, Exercise, and Temperature
• Three things demonstrated by the relationship of the oxygen dissociation curve: 1. Progressive increase in the percentage of hemoglobin bound with oxygen as blood PO2 increases 2. In the lungs with blood PO2 at 100 mmHg, hemoglobin is 97% saturated with oxygen 3. In venous circulation with PO2 at 40 mm Hg, hemoglobin molecule is 75% saturated with oxygen and 25% of the oxygen is capable of being released when the hemoglobin level is normal
• The following factors will affect the oxygen dissociation curve: Allosteric Effectors 1. Heme-heme interactions 2. Bohr effect (Hydrogen and pH) 3. Effect of 2,3-bisphosphoglycer
• Hemoglobin molecule is 75% saturated with oxygen and 25% of the oxygen is capable of being released when the hemoglobin level is normal
• Factors affecting the oxygen dissociation curve

  • Heme-heme interactions
  • Bohr effect (Hydrogen ve pH)
  • Effect of 2,3-bisphosphoglycerate on oxygen affinity
  • Binding of CO2
  • Binding of CO
• Allosteric Effectors


  Factors that affect the binding of oxygen to heme groups at other locations on the hemoglobin molecule
• The Bohr Effect is the influence of pH and pCO2 to facilitate oxygenation of Hb in the lungs and deoxygenation at the tissues
• Binding of CO2

  Forces the release of O2
• CO2 and H+ decrease the affinity of Hb to O2. This is the Bohr Effect
• Decrease in Ph, Increase in H+, Increase pCO2

  Shifts the standard curve to the right
• The Bohr Effect explains how hydrogen ions and carbon dioxide affect the affinity of oxygen in Hemoglobin
• R → T change

  The affinity of hemoglobin for O2 is decreased (the ODC is shifted to the right) and so, more O2 is released to the tissues