Cooperativity

This implies that:

Binding sites exist for more than one ligand.

Binding of each ligand facilitates binding of successive ligands.

With partial saturation of haemoglobin with oxygen, the affinity of the remaining haems on the tetramer for oxygen increases markedly. This is because alpha 1 beta 2 interface destabilisation causes the transition of the quaternary structure from the T (tense or taut form) to the R (relaxed) state.

Oxygen has significantly higher affinity for haemoglobin in the R state.

Oxygen binding stabilises the T state.

Oxyhaemoglobin and deoxyhaemoglobin differ markedly in quaternary structure. The Perutz mechanism is a description of the dynamic behaviour of haemoglobin based largely on the static structure of its R and T end states. The quaternary structure of deoxyhaemoglobin is the T form, with low affinity for oxygen; that of oxyhaemoglobin the R form, with high affinity. Changes in conformation of Fe2+ trigger a sequence of intermolecular rearrangements. The contacts between the haemoglobin subunits are described as the aip2 and the aipi regions. The aipi contact change is slight. The aip2 contact region is designed to act as a switch between two alternative structures. When oxygen is absent experimentally, the T state is more stable and is thus the predominant configuration of deoxyhaemoglobin.

The T to R transition is triggered by changes in the positions of key amino acid side chains surrounding the haem. The T state is stabilised by a network of C-terminal salt bridges that must break to form the R state.

The allosteric properties of haemoglobin arise from interactions between its subunits. Allosteric theory explains haem-haem interaction without postulating any direct communication between the haem groups. The functional unit of haemoglobin is a tetramer consisting of two kinds of polypeptide chains. A structural change (oxygenation) within a subunit is translated into structural changes at the interfaces between subunits. Binding of oxygen at one haem site is thereby communicated to parts of the molecule that are far away.

Shift of the HbO2 dissociation curve to the right implies increased tissue oxygen delivery, reduced oxygen affinity of haemoglobin (fall in P50) and a more sigmoid shape. P50 is the pO2 at which haemoglobin is 50% saturated with oxygen under standard conditions of temperature and pH.

Causes of shift to the right:

Carbon dioxide with increase in H+

Hydrogen ions-protons (Bohr shift), associated with a fall in pH (acute acidosis). Haemoglobin binds one H+ for every two oxygen molecules released. This favours the conversion of carbon dioxide into the bicarbonate ion promoting its transport back to the lungs.

2,3-Diphosphoglycerate (depletion of intracellular 2,3-DPG in stored blood may impair tissue oxygen delivery with transfusion).

Rise in intracellular pH.

Increased temperature.

Causes of shift to the left (increased P50):

Reduction in temperature.

Increased oxygen tension: Haldane effect.

Reduced H+ and paCO2: rise in pH and fall in paCO2.

Increased CO tension: carbon monoxide has 150 times the affinity of oxygen for the haem iron.

Fetal haemoglobin: binds oxygen more strongly than maternal haemoglobin. The difficulty in oxygen release is compensated for by higher haemoglobin concentrations in the fetus.

Carboxyhaemoglobin.

Methaemoglobin.

Fall in intracellular adenosine triphosphate (ATP).

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