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Haemoglobin
Written by Tim Sheppard MBBS BSc. Created 17/4/10; last updated 5/7/12

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What is haemoglobin?

Haemoglobin (or, as spelt in America, hemoglobin) is a chemical found in red blood cells which is essential for carrying oxygen from the lungs to the rest of the body. In fact, it is a protein with a special structure (a quarternary structure) designed to help it in this important role.

The best way to think about it is probably to think of oxygen as a very valuable item which needs to be taken from one place to another. To do this, it needs to be carried in special packaging - in this case, haemoglobin. Not all of the oxygen in the blood is bound to haemoglobin; some of it is just dissolved in the blood. But in order to make sure that the blood can carry as much oxygen as possible, red blood cells are packed full of this chemical so that it can bind as much oxygen as possible - and without this chemical (e.g. when you become anaemic), the body finds that it can't get as much oxygen as it would like.

The most common form of haemoglobin (haemoglobin A) is made up of four major parts - two alpha (α) subunits, and two beta (β) subunits. Each of these units is a long stretch of protein that is mainly coiled up into eight alpha helices. The hydrophobic amino acids in this stretch of protein group together in the centre of the subunit to hide a haem group, while the hydrophilic amino acids are on the surface.

This chemical, known as 2,3 BPG, binds to haemoglobin in the middle in a special way that makes it less able to bind to oxygen; it means that it can affect the ability of haemoglobin to do its job, and so it's an example of allosteric regulation.

The haem group is what makes haemoglobin so exciting. The haem group is basically a ring of mainly carbon atoms with an iron ion (Fe2 ) wrapped up in the middle. The shape of each haemoglobin subunit means that this haem group is found in a pocket in the centre, kept nice and safe. So you have subunits containing haem groups containing an iron ion. Why is that even remotely important?

The reason it's important is because it's with this haem group that haemoglobin is able to get hold of oxygen. You see, the idea is that haemoglobin will form a chemical bond with oxygen, but it won't form a tight, immovable bond with it - it needs to drive the oxygen to the right place and then let it go, not handcuff itself to the oxygen and then throw away the key.

This haem group provides the solution. The iron ion has the opportunity to bind to six different things, and give of its bonds are already taken up. The oxygen is able to form a co-ordinate covalent bond with oxygen, transported around the body until it gets to the right place. Then, because the oxygen concentration is so much lower, it will be released into the tissues.

Interestingly, it is because this haem group contains iron (a transition metal) that red blood cells have the colour that we so strongly associate with blood. Haem can be found in other parts of the body too - for example, as part of one of the proteins in the electron transport chain, or in the substantia nigra in the brain.


What else binds to haemoglobin?

Haemoglobin is cleverly set up to act as a really useful transporter in the blood - so although its most important job is transporting oxygen, it is also able to bind to other things.

One of these other things is carbon dioxide. Carbon dioxide is a waste product of metabolism, when energy is obtained from food. This carbon dioxide needs to make it's way to the lungs, and it can do this dissolved in the plasma - but it also binds to the protein chains of haemoglobin so that even more can be carried. Carbon dioxide binds to haemoglobin to form carbaminohaemoglobin, because it binds to an amino group in one of haemoglobin's amino acids. Carbon dioxide does not stop oxygen binding to haemoglobin because they bind in different places, but it does change how readily haemoglobin binds to oxygen. The two are connected by the Bohr and Haldane effects.

Unlike carbon dioxide, carbon monoxide does compete with oxygen for the same binding site to form carboxyhaemoglobin. This means that carbon monoxide gas is poisonous, because it reduces the amount of oxygen that is able to get into the blood. In fact, carbon monoxide binds more strongly with haemoglobin than oxygen does, so even a small amount of carbon monoxide is bad news. Because the two gases are competing for the same place, the best way to treat carbon monoxide poisoning is by giving so much oxygen that there's no room for the carbon monoxide to get in.

There are many things which can bind to haemoglobin, but other important ones to notice are hydrogen, glucose, and 2,3 BPG. Hydrogen is important because haemoglobin acts as a buffer - opposing changes in the amount of free hydrogen floating around by binding to it. Glucose is important because the amount of haemoglobin bound to glucose can be measured as an HbA1c, which gives an indication of how much glucose has been floating around over the past 3 months (and thereby giving an indication of how well a diabetic patient's blood glucose has been controlled). The reason 2,3 BPG is important is because when it binds to a haemoglobin molecule, it reduces its ability to bind to oxygen.


What other forms of haemoglobin are there?

Haemoglobin is actually a name given to a lot of similar proteins with the same purpose - carrying around oxygen. However, there are a number of different forms - some completely normal, some abnormal, which are important to know about.

When a baby is growing in his mother's womb, he needs to make sure that his blood grabs hold of the oxygen that's in his mum's blood! Stealing oxygen isn't easy when haemoglobin is so readily bound to it. In part, the baby is able to achieve it simply because the oxygen levels are so low in the baby - oxygen will travel there by simple diffusion. However, in addition to that, the baby's haemoglobin is a different type.

For the first three months, you get embryonic haemoglobin or Hbemb - which comes as one of three types, Gower 1, Gower 2 or Portland. The basic difference is that each one uses different subunits. Instead of α and β subunits, you get ζ and ε (Gower 1), α and ε (Gower 2), or ζ and γ (Portland) subunits. In every case, you get two of each subunit.

For the rest of pregnancy, you get a build up of foetal haemoglobin or HbF - two α chains and two γ chains. Again, the whole point is that this type of blood will take oxygen from the haemoglobin of the adult mother. In terms of the oxygen-haemoglobin dissociation curve, there is a shift to the left, so that oxygen is more readily bound.

Although more than half of the haemoglobin that a baby is born with is foetal haemoglobin, the baby already has some 'adult haemoglobin' (haemoglobin A). Over time, almost all of the foetal haemoglobin is replaced with adult haemoglobin, and you end up with 95% HbA. There is, still, a smaller amount of haemoglobin A2, made up of two α and two γ chains - which acts in much the same way as normal haemoglobin.

Sometimes genetic differences in haemoglobin protect people from blood-borne diseases like malaria, and so even though they are less effective at carrying oxygen, they still survive. One common example of this is sickle cell anaemia, where a mutation in the beta chain leads to glutamate swapping with valine in position 6, to produce haemoglobin S (HbS). The changed structure leads to a risk of blood cells turning into sickle-shaped cells (hence the name) when they give up their oxygen; but this also protects against severe malaria. This means that African populations have a particularly high incidence of HbS. A similar observation is seen with haemoglobin C (HbC), where lysine swaps with the glutamate to produce another variant that protects against severe malaria.

Methaemoglobin is not a change in the genetics or the subunits of haemoglobin, but is important and well-worth a mention. It is a form of haemoglobin where the iron is in the form Fe3+ instead of Fe2+. It sounds like only a small change, but it's pretty important because the change stops haemoglobin from being able to bind to oxygen. This is disasterous if it stops you from getting enough oxygen around the body. However, in cases of cyanide poisoning it can sometimes be utilised because methaemoglobin binds to cyanide and enables disposal of it - provided the fall in oxygen carrying ability doesn't kill you first!


What is the oxygen-haemoglobin dissociation curve?

The oxygen-haemoglobin dissociation curve is a graph that gives us an idea of how well haemoglobin binds to oxygen given a particular concentration of oxygen. The more oxygen floating around, the more oxygen that haemoglobin binds to. But it's not simple - it doesn't just go up in a straight line. When the first molecule of oxygen binds to oxygen, it opens up haemoglobin to make it easier for others to bind. Since binding to haemoglobin makes a difference to how well other molecules can bind, the ease at which haemoglobin binds changes depending on concentration.

The graph compares oxygen saturation (the percentage of haemoglobin that has as much oxygen bound to it as it can) with the partial pressure of oxygen (or oxygen tension) - basically a measure of how much oxygen is around. If we start from 0, when there's no oxygen around, no oxygen is bound to haemoglobin. As the oxygen builds up, we eventually reach a point where one molecule can bind. When that has bound, it encourages its friends - two and three - to join it. The fourth (and last) oxygen molecule is the difficult one, because there's no room left at the party, but eventually that one joins too.

The curve is an "S" shape - or sigmoidal. This is an important and common shape in maths. It basically means that to begin with binding is difficult, then it gets easy, then when there's no space left it becomes difficult again. It might sound complicated or unimportant, but in fact it is a really key thing to understand, because we rely on oxygen saturations to guess how much oxygen is in the blood. The fact is, the changing shape of this curve means that it's much harder to guess what the pO2 is if you are looking at the oxygen saturations. Let me explain.

If you're starting at 100% oxygen saturation, a small drop in oxygen saturations means an enormous drop in partial pressure of oxygen - the curve is flat at this point, so a tiny drop in saturation takes you a long way along the curve. What seems like a small drop in haemoglobin saturation from 100% to 95% actually means the partial pressure has dropped by much more! It's a bit like the tide coming in on a flat beach; if the tide rises by 1 inch on a flat beach, it will come in a really long way despite how little it has risen.

The shape also means that if the concentration of surrounding oxygen continues to drop, you'll eventually get a very rapid drop in haemoglobin saturation too. If there's little oxygen floating around and little bound to haemoglobin, you really do have a problem!!

Before you go any further, make sure you've understood the curve so far. It's about to get a tiny bit more complicated.

The oxygen-haemoglobin dissociation curve can change. It doesn't change shape very much - it is still the S-shape which we've seen so far. But it can shift towards the left or the right in certain conditions. What does that mean?

In conditions where the temperature is higher, or there is a higher concentration of hydrogen (i.e. a lower pH), or there is a higher concentration of a chemical called 2,3-BPG (2,3-bisphosphoglycerate), the curve shifts to the right. This means that at any given partial pressure of oxygen, the saturation will be lower. In other words, when these things are higher, haemoglobin doesn't bind to oxygen so well.

On the other hand, in conditions where the temperature is lower, or there is a lower concentration of hydrogen (a higher pH), or there is a lower concentration of 2,3-BPG, the curve shifts to the left. This means that at any given partial pressure of oxygen, the saturation will be higher. When these things are lower, haemoglobin binds to oxygen more keenly.

Shifts of the oxygen-haemoglobin dissociation curve are important to understand, not least because they form the basis of the Bohr and Haldane effects.


What are the Bohr and Haldane effects?

The Bohr effect was identified by Christian Bohr, a Danish scientist who realised that the amount of oxygen that haemoglobin binds - indeed, the whole of the oxygen-haemoglobin dissociation curve - was affected by the amount of hydrogen or carbon dioxide around.

The oxygen-dissociation curve gives an impression of how well oxygen binds to haemoglobin given a particular partial pressure of oxygen in the solution around it. The higher the partial pressure of oxygen, the more that you will find bound to haemoglobin. The thing is, even though carbon dioxide and hydrogen don't bind in the same place as oxygen, when they do bind to haemoglobin they cause a slight change in the shape of the molecule. This means that as the concentration of hydrogen goes up (or the pH goes down), or the concentration of carbon dioxide rises, haemoglobin is happier without oxygen. Similarly, where there is more oxygen, carbon dioxide and hydrogen are more likely to let go.

This means that the oxygen-haemoglobin dissociation curve shifts to the right when there is more hydrogen or carbon dioxide floating around. A shift to the right means that, at any given partial pressure of oxygen, there will be less oxygen bound to haemoglobin (i.e. lower saturations).

This may sound like a bad thing - but in fact it is brilliant news. Carbon dioxide is produced in metabolism, so places in the body which are really active are going to be producing a lot of carbon dioxide. They are also places that will need a lot of oxygen. So, when blood gets to these really active places, the high concentration of carbon dioxide will cause the haemoglobin to release the oxygen (because it doesn't bind to it easily anymore) - leaving the oxygen available for the active tissues to use in metabolism. At the same time, the haemoglobin picks up the carbon dioxide and takes it to the lungs.

This effect is made even greater because of the carbonic acid equilibrium. The carbonic acid equilibrium is a little bit complicated, but it basically means that if the carbon dioxide concentration in blood goes up, more hydrogen ions will be produced to try to oppose the change in carbon dioxide concentration. In other words, where there is more carbon dioxide, there is more hydrogen - increasing the Bohr effect even more.

At the lungs, the high concentration of oxygen and low concentration of carbon dioxide and hydrogen means that the reverse happens - the carbon dioxide leaves the haemoglobin, and the curve shifts back to the left - making it very keen to bind some more oxygen. The high concentration of oxygen is therefore readily snatched up by the blood and taken back to the tissues.

The Haldane effect, identified by John Scott Haldane, considers the link from the other perspective. Rather than asking how readily does haemoglobin bind to oxygen, it asks how readily haemoglobin binds to carbon dioxide. The Haldane effect is the observation that the less oxygen bound to haemoglobin, the more carbon dioxide will; conversely, the more oxygen bound to oxygen, the less carbon dioxide will be. This is another way of helpfully understanding why the oxygen and carbon dioxide bind and separate from haemoglobin in the places that they do.

The thing to remember is that a change in the oxygen-haemoglobin curve doesn't destroy the oxygen, it simply changes where it is - and in the case of the Bohr and Haldane effects, they help to make sure all of the molecules are in the best place.


Further Reading