Sunday, 16 December 2007

The haemoglobin story (Part 2)

At the end of part 1, we had a structure that transported oxygen in the blood stream (which was necessary due to oxygen's poor native solubility in blood) whilst preventing it from reacting with the structure on the way. However, we had run into an obstacle: the oxygen transport protein, haemoglobin, ideally needed to have a different affinity for oxygen depending on whether it was in the lungs or in the tissues. At the lungs, it needed to be merciless in its theft of nearby oxygen molecules. However, at the tissues, it suddenly needed to be equally generous in its releasing of the very molecules it had held onto so tightly just a few seconds earlier.

Haemoglobin does solve this difficulty, of course - it has to! But how?

The first thing to understand is that the problem isn't quite as bad as it seems. The amount of oxygen bound to haemoglobin depends on the concentration of oxygen in the blood at any time. In other words, the equation looks something like this:

deoxygenated Hb + O2 ⇌ oxygenated Hb

(where Hb is the accepted abbreviation for haemoglobin)

When oxygen is plentiful, the equation will be driven to the right; more oxygen binds. When that oxygenated Hb molecule moves to a location where there is less oxygen around, some of its bound oxygen detach and move back into solution. This much is not new - something similar must happen to any two things whose binding is reversible. So, just by being in the lungs, oxygen would tend to bind to haemoglobin. And just by moving to the tissues, some of this oxygen would detach automatically.

Does that solve the problem? Well, it does allow for a passable form of an oxygen transport protein, but it would still clearly be much better if its affinity for oxygen could change, wouldn't it? Otherwise, we would have either a protein that was great at taking oxygen from the air, but awful at releasing it to the tissues, or else a protein that was incredibly resistant to binding the oxygen in the lungs, leading to a situation (similar to when we didn't have an oxygen transport protein) of relying mostly on dissolved oxygen reaching the tissues. We've have already identified the latter option as being physiologically disastrous.

Hold on, here's an idea though. What if we used the fact that oxygen tends to bind in the lungs and detach at the tissues as a signal. In other words, what if the act of oxygen binding to haemoglobin increased the affinity of other haemoglobin molecules for oxygen? Similarly, if the oxygen detached, this could be a signal to a haemoglobin molecule's colleagues to do the same. In this way, we could alter the affinity in the correct ways at the correct places. Perfect!

Alas, there is one more problem to be solved. Just how is haemoglobin supposed to signal to the other haemoglobins to change their affinities? Each molecule is an isolated individual, and communication between them would require complicated machinery on each.

As ever, the solution is more elegant. Haemoglobin is really a tetramer consisting of four subunits. Each subunit consists of a haem group surrounded by the globin protein, in a structure mentioned in Part 1. It's just that this motif is repeated four times in each haemoglobin molecule. (Diagram below - subunits in blue and red, with the haem parts in green...)

What this does, of course, is to solve our communication problem. When oxygen binds to one of the four subunits, communicating to the others to increase their affinities is virtually effortless. This is sometimes termed cooperative binding. And when oxygen detaches itself at the tissues, the first subunit to lose its oxygen can similarly signal to the others to decrease their affinities too. And when the second subunit follows the first's lead, the remaining subunits' affinities are decreased further, and so on.

Truly amazing isn't it? The effect of these shifting affinities is the famous 'sigmoid' (S-shaped) graph of oxygen saturation vs oxygen partial pressure. (The latter is merely a measure of how much oxygen is sitting around the haemoglobin molecules; it is thus high in the lungs and low at the tissues.)

Oh, one last thing? Why package the haemoglobin molecules into a cell (the well-named red blood cells)? Not all animals do so; some simply have it floating freely in the plasma. But in these cases "about 3 percent leaks through the capillary membrane into the tissue spaces or through the glomerular membrane of the kidney into the glomerular filtrate every time the blood passes through the capillaries." (Textbook of Medical Physiology, 10th Edn. Guyton and Hall)

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