oxygen transporting proteins

Lecture 4
Oxygen transport proteins
Dr. Hadeel A. Kerbel
Lecture 4: Learning outcomes
1. Explain the physiological roles of myoglobin and
haemoglobin.
2. Contrast the oxygen?binding properties of myoglobin
and haemoglobin and explain why haemoglobin is most
suited to its role as an oxygen transporter.
3. Describe the major structural differences between
oxygenated and deoxygenated haemoglobin and the
molecular basis of cooperativity.
4. Describe the effects of CO2, H+,
2’3bisphosphoglycerate and carbon monoxide on the
binding of oxygen by haemoglobin, and the physiological
significance of these effects.
5. Appreciate that mutations in globin genes can give rise
to diseases such as sickle cell anaemia or thalassemia.
Structure of heme
• Heme is a complex of protoporphyrin IX and
ferrous iron (Fe2+).
• The iron is held in the center of the heme
molecule by bonds to the four nitrogens of the
porphyrin ring.
• The heme Fe2+ can form two additional
bonds, one on each side of the planar
porphyrin ring.
• In myoglobin and hemoglobin, one of these
positions is coordinated to the side chain of a
histidine residue of the globin molecule,
whereas the other position is available to bind
oxygen
Structure and function of myoglobin
• Myoglobin, a hemeprotein present in heart
and skeletal muscle.
• functions both as a reservoir for oxygen and
as an oxygen carrier that increases the rate of
transport of oxygen within the muscle cell.
• consists of a single polypeptide chain that is
structurally similar to the individual
polypeptide chains of the tetrameric
hemoglobin molecule.
• approximately 80% of its polypeptide chain
folded into eight stretches of ??helix. These ??
helical regions, labeled A to H.
• The interior of the myoglobin molecule is
composed almost entirely of nonpolar amino
acids.
• polar amino acids are located almost
exclusively on the surface.
Binding of the heme group
• The heme group of the myoglobin molecule sits
in a crevice, which is lined with nonpolar amino
acids.
• exceptions are two histidine residues.
• One, the proximal histidine (F8), binds directly to
the iron of heme.
• O2 is bound directly only to Fe in heme, on the
opposite side to His F8
• Histidine E7 (distal His) does not directly interact
with the heme group, but helps stabilize the
binding of Oxygen to the ferrous ion.
Structure and function of hemoglobin
• Hemoglobin (Hb) subunits and myoglobin are
similar in their helical structure and in heme
binding pocket. However, the tetrameric
hemoglobin molecule is structurally and
functionally more complex than myoglobin.
• Hb can carry 4 O2 from lungs to the cells of the
body.
• It also can transport H+ and CO2 from the tissues
to the lung.
• The oxygen?binding properties of Hb are
regulated by interaction with allosteric effectors.
Quaternary structure of hemoglobin
• The hemoglobin tetramer can be envisioned
as being composed of two identical dimers,
(??)1 and (??)2.
• The two polypeptide chains within each dimer
are held tightly together primarily by
hydrophobic interactions.
• Transition from T to R state in haemoglobin On
binding oxygen, one pair of ?? ?subunits shifts
with respect to the other by a rotation of 15
degrees.
• Binding of oxygen to one subunit ‘switches’ other
subunits to a conformation which favours oxygen
binding ? leading to ‘cooperative’ binding of
oxygen.
Oxygen Dissociation Curves for
myoglobin and hemoglobin
• The degree of saturation(Y) of O2
binding sites on all myoglobin or
hemoglobin molecules can vary
between zero (all sites are empty)
and 100% (all sites are full)
• A plot of Y measured at different
partial pressures of O2 is called
Oxygen Dissociation Curve.
Oxygen Dissociation Curves for
myoglobin and hemoglobin
Myoglobin has a higher oxygen affinity than does
hemoglobin.
•The partial pressure of oxygen needed to achieve halfsaturation
of the binding sites (P50) is approximately 1
mm Hg for myoglobin and 26 mm Hg for hemoglobin.
•The higher the oxygen affinity (that is the more tightly
oxygen binds), the lower the P50
•a hyperbolic relationship between Y and pO2 for
myoglobin.
•A sigmoidal relationship between Y and pO2 for Hb
(cooperative).
• Myoglobin hyperbolic shape
myoglobin reversibly binds a single molecule
of oxygen.
• Hemoglobin sigmoidal in shape.
• indicating that the subunits cooperate in
binding oxygen.
• Cooperative binding of oxygen by the four
subunits of hemoglobin means that the
binding of an oxygen molecule at one heme
group increases the oxygen affinity of the
remaining heme groups in the same
hemoglobin tetramer.
Regulation of oxygen binding
• The affinity of hemoglobin for the last oxygen
bound is approximately 300 times greater
than its affinity for the first oxygen bound.
• Loading and unloading oxygen: The cooperative
binding of oxygen allows hemoglobin to deliver
more oxygen to the tissues in response to
relatively small changes in the partial pressure of
oxygen.
• Significance of the sigmoidal oxygen?dissociation
curve permits hemoglobin to carry and deliver
oxygen efficiently from sites of high to sites of low
pO2.