Developmental Changes in Hb Globin Makeup

                     alpha-like           beta-like

(<8 weeks)           zeta2 -> zeta1     epsilon

(8-41 weeks)         alpha                gammaG -> gammaA

(birth-death)        alpha                beta and (some) delta

For convenience, the different flavours are also referred to as 'zeta globin', 'gamma globin' and 'alpha-beta globin' (or simply unqualified 'h(a)emoglobin') respectively.

Globular protein, found in red blood cells, it combines with oxygen to form oxyhaemoglobin, which is a bright red colour, it can combine with four oxygen molecules, and will release them at low partial pressures of oxygen (such as in respiring tissues) and take it up at high partial pressures of oxygen (such as the lungs). It is made up of four polypeptide chains and four prosthetic haem (heme) groups (these contain iron, and are the primary use of iron in the body). There are several different types of h(a)emoglobin, such as foetal haemoglobin and haemoglobin from differnet animals, which differ mainly in their disociation curves (name for the graph of the partial pressure of oxygen against the percentage saturation of the haemoglobin molecules ie. how much oxygen it takes up at different partial pressures). Haemoglobin also combines with carbon dioxide to form carbaminohaemoglobin, and with carbon monoxide irreversably to form carboxyhaemoglobin, which can seriously reduce the oygen-carrying capacity of the blood.

The degree to which heamoglobin is adapted to its environment is incredible. High altitude animals, such as llamas have heamoglobin that binds releases heamoglobin at lower partial pressures than human haemoglobin, so it is better able to cope with the low levels of oxygen in the air. Crocodile heamoglobin, which is one of the primary reasons they can stay underwater for up to 30 minutes at a time has a version of haemoglobin that is sensitive to bicarbonate ions, which build up in the blood as the crocodile goes underwater. This causes the haemoglobin to bind tighter to the oxygens and only release them at lower partial pressures, effectively streching out the crocodile's oxygen supply.

Hemoglobin is a globular protein, which in adults contains two alpha subunits and two beta subunits. The protein is composed of two alpha-beta dimers. These subunits closely resemble myoglobin, a protein with 153 amino acid residues in 8 α-helicies labeled A-H. The alpha subunit has 141 amino acid residues, it lacks helix D and has a shortened helix H. The beta subunit has 146 amino acid residues, and has a shortened helix H.

Each subunit contains a heme molecule, which is an aromatic ring structure that is composed of four pyrrole rings linked by methelyene bridges. The heme group has an iron atom coordinated by the four nitrogen atoms of each pyrrole ring.

The iron atom is in the ferrous, Fe(II), oxidation state. It coordinates six ligands (with oxygen bound) and has an octahedral geometry. If the iron atom is oxidized to the ferric, Fe(III) state, the iron will coordinate a water molecule instead of an oxygen molecule. This oxidation does not occur upon the binding of oxygen when the heme is located in the protein. If it does occur then hemoglobin is called methemoglobin. The enzyme methemoglobin reductase will catalyze the conversion of the iron back to the Fe(II) state.

Iron Ligands
Four Nitrogen atoms of pyrrole rings
Proximal Histidine F8
Oxygen (When bound)

The oxygen binding site is sterically hindered by the distal histidine E7.

The distal histidne plays an important role in carbon monoxide binding. When stripped of protein the heme will bind CO with 25,000 times the affinity of oxygen. In the protein this is reduced to 250 times the affinity. This is due to steric interactions of the distal histidine E7. CO binds optimally at an angle of 90 degrees with respect to the heme plane. Histidine E7 forces CO to bind at a 60 degree angle greatly decreasing its affinity

Hemoglobin exists in two conformational states. The T-state, which has a low affinity for oxygen, and the R-state, which has a high affinity for oxygen. Each state is stabilized by a particular set of forces. Upon oxygen binding the T-state shifts to the R-state and when oxygen unbinds the R-state shifts to the T-state.

These conformational changes occur because in the T-state the Fe atom is located .6 angstroms out of the heme plane. When oxygen binds this pulls the iron in towards the heme plane by .4 angstroms. This causes a shift in the location of the F helix which disrupts the stabilizing interactions of the T-state and forms the stabilizing interactions of the R-state.

Factors Involved in Conformational Shifts
Bohr Effect
Salt Bridges
Carbamylation of the N-Terminus
Binding of Bisphosphoglycerate

Hemoglobin demonstrates one of my favorite phenomenons in biology, cooperativity.

The binding curve, or the affinity of oxygen to a single hemoglobin subunit is mostly linear - meaning that if the amount of oxygen bound to hemoglobin changes only linearly with the amount of oxygen present. This is not useful - the amount of oxygen in the lungs is not dramatically different than in the brain (and other parts of the body), but you want the hemoglobin to bind oxygen in the lung, and release it in the brain.

Hence cooperativity - hemoglobin is a tetramer, being made of 4 subunits. The affinity of each subunit to oxygen is affected by the other subunits. This results in a change in the binding curve. Through evolution, the now cooperative binding curve is such that hemoglobin binds oxygen strongly at oxygen concentrations found in the lung, while it releases oxygen well at only slightly lower oxygen concentrations.

Basically, the cooperativity changes the linear (or at least low-order) phenomena found in most chemical systems to a high-order, almost binary phenomena found in many biological systems.

To expand upon the excellent writeups already in this node, a hemoglobin molecule contains heme as a prosthetic group and is composed of four polypeptides. The types of these polypeptide chains are called alpha, beta, gamma, and delta, and they affect the structure and function of the molecule.

Here are the different types of hemoglobin, based on their chain structures:

Hemoglobin A is the normal form of the protein hemoglobin which is found in adults. It is composed of two alpha chains and two beta chains.

Hemoglobin C is an abnormal version of the protein. The sixth amino acid of the normal beta chain, glutamic acid, is replaced by lysine in hemoglobin C. This mutation causes the red blood cells to be less flexible.

Hemoglobin E is also an abnormal version of the protein; it is most often found in people of Southeast Asian descent. E plays a role in medical conditions such as microcythemia and mild hemolytic anemia. The beta chain of the hemoglobin molecule is altered because of a mutation.

Hemoglobin F is the normal form of the protein which is found in the fetus.

Hemoglobin H is an abnormal version and is composed of four beta chains. The molecule has a very high affinity to oxygen, but is very inefficient at transporting it.

Hemoglobin S is an abnormal version. The sixth amino acid of the normal beta chain, glutamic acid, is replaced by valine with gluconic acid. This mutation causes the red blood cells to take on a sickle shape, and is the cause of the sickle cell trait condition (when the individual is heterozygous for this mutant hemoglobin) and the disease of sickle cell anemia (when the individual is homozygous for this mutant hemoglobin).

From the science dictionary at

Foetal Haemoglobin

A developing foetus obtains oxygen not from its own lungs, but from its mother's blood. In the placenta, the mother's blood is brought very close to that of the foetus, allowing diffusion of various substances from mother to foetus or vice versa.

Oxygen arrives at the placenta in combination with haemoglobin, inside the mother's red blood cells. The partial pressure of oxygen in the blood vessels in the placenta is relatively low, because the foetus is respiring. The mother's haemoglobin therefore releases some of its oxygen, which diffuses from her blood into the foetal blood.

The partial pressure of oxygen in the foetal blood is only a little lower than that in its mother's blood. However, the foetal and maternal haemoglobin have different structures: foetal haemoglobin combines more readily with oxygen than does maternal, so the foetal haemoglobin will thus 'pick up' oxygen which the maternal haemoglobin has 'dropped'. Foetal haemoglobin is said to have a higher affinity for oxygen than adult haemoglobin.

Acoordingly, a dissociation curve for foetal haemoglobin shows that, at each partial pressure of oxygen, foetal haemoglobin is slightly more saturated than adult haemoglobin.

Hem"o*glo"bin (?), n. [Hemo- + globe.] Physiol.

The normal coloring matter of the red blood corpuscles of vertebrate animals. It is composed of hematin and globulin, and is also called haematoglobulin. In arterial blood, it is always combined with oxygen, and is then called oxyhemoglobin. It crystallizes under different forms from different animals, and when crystallized, is called haematocrystallin. See Blood crystal, under Blood.


© Webster 1913.

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