3-dimensional structure of hemoglobin
Haemoglobin (BE) or hemoglobin (AE), is the iron-containing oxygen-transport metalloprotein in the red cells of the blood in mammals and other animals. The molecule consists of globin, the apoprotein, and four haem groups, an organic molecule with an iron atom.
Mutations in the gene for the haemoglobin protein result in a group of hereditary diseases termed the hemoglobinopathies, the most common members of which are sickle cell anaemia and thalassaemia.
At the core of the molecule is a heterocyclic
ring, known as a porphyrin
which holds an iron atom; this iron atom is the site of oxygen binding. An iron containing porphyrin is termed a heme
. The name hemoglobin
is the concatenation of heme
, a globin
being a generic term for a globular protein
. Since a single subunit
of hemoglobin is, in fact, made of a heme imbedded in a globular protein, the name makes sense. There are a number of heme containing proteins
. Hemoglobin is by far the best known.
In adult humans, hemoglobin is a tetramer (contains 4 subunit proteins), consisting of two alpha and two beta subunits noncovalently bound. The subunits are structurally similar and about the same size. Each subunit has a molecular weight of about 16,000 Daltons, for a total molecular weight in the tetramer of about 64,000 Daltons. Each subunit of hemoglobin contains a single heme, so that the overall binding capacity of adult human hemoglobin for oxygen is four oxygen molecules:
- Hb + O2 <-> HbO2
- HbO2 + O2 <-> Hb(O2)2
- Hb(O2)2 + O2 <-> Hb(O2)3
- Hb(O2)3 + O2 <-> Hb(O2)4
Binding of ligands
In the tetrameric form of normal adult hemoglobin, the binding of oxygen is a cooperative process. The binding affinity of hemoglobin for oxygen is increase by the oxygen saturation of the molecule. As a consequence, the oxygen binding curve of hemoglobin is sigmoidal, or 'S' shaped, as opposed to the normal hyperbolic (noncooperative) curve. This positive cooperative binding is achieved through steric conformational changes of the hemoglobin protein complex: when one subunit protein in hemoglobin becomes oxygenated it induces a confirmation or structural arrangement change in the whole complex causing the other 3 subunits to gain an increased affinity for oxygen.
Hemoglobin's affinity for oxygen is decreased in the presence of carbon dioxide and at lower pH. Carbon dioxide reacts with water to give bicarbonate, carbonic acid freed protons via the reaction:
- CO2 + H2O <-> HCO3- + H+
So blood with high carbon dioxide levels is also lower in pH (more acidic). Hemoglobin can bind protons and carbon dioxide which causes a conformational change in the protein and facilitates the release of oxygen. Protons bind at various places along the protein and carbon dioxide binds at the alpha-amino group forming carbamate. Conversely, when the carbon dioxide levels in the blood decrease (i.e. around the lungs), carbon dioxide is released, increasing the oxygen affinity of the protein. This control of hemoglobin's affinity for oxygen by the binding and release of carbon dioxide is known as the Bohr effect.
The binding of oxygen is affected by molecules such as carbon monoxide (CO) (For example from tobacco smoking, cars and furnaces). CO competes with oxygen at the heme binding site. Hemoglobin binding affinity for CO is 200 times greater then its affinity for oxygen, meaning that small amount of CO can dramatically reduces hemoglobinís ability to transport oxygen. Hemoglobin also has competitive binding affinity for Sulfur monoxide (SO), Nitrogen Dioxide (NO2) and Hydrogen sulfide (SH2).
In people acclimated to high altitudes, the concentration of 2,3-diphosphoglycerate (2,3-DPG) in the blood is increased, which allows these individuals to deliver a larger amount of oxygen to tissues under conditions of lower oxygen tension. This phenomenon, where molecule Y affects the binding of molecule X to a transport molecule Z, is called a heterotropic allosteric effect.
A variant hemoglobin, called fetal hemoglobin (HbF, α2γ2), is found in the developing fetus, and binds oxygen with greater affinity than adult hemoglobin. Consequently, the oxygen binding curve for fetal hemoglobin is left-shifted (i.e., a higher percentage of hemoglobin has oxygen bound to it at lower oxygen tension) in comparison to that of adult hemoglobin.
Degradation of haemoglobin
When red cells reach the end of their life, they are broken down, and the haemoglobin molecule broken up and the iron recycled. When the porphyrin ring is broken up, the fragments are normally secreted in the bile by the liver. The major final product of heme degradation is bilirubin. Increased levels of this chemical are detected in the blood if red cells are being destroyed more rapidly than usual. Improperly degradated hemoglobin protein or hemoglobin that has been released from the blood cells can clog small blood vessels especially the delicate blood filtering vessels of the kidneys, causing kidney damage.
Other Biological Oxygen-Binding Proteins
It should be noted that hemoglobin is by no means unique. There are a variety of oxygen transport and binding proteins throughout the animal (and plant) kingdom.
Myoglobin: Found in the muscle tissue of many vertebrates including humans (gives muscle tissue a distinct red or dark gray color). Is very similar to hemoglobin in structure and sequence, but is not arranged in tetramers and lacks cooperative binding and is used to store oxygen rather then transport it.
Hemocyanin: Second most common oxygen transporting protein found in nature. Found in the blood of many arthropods and molluscs. Uses copper prosthetic group instead of iron heme groups and is blue in color when oxygenated.
Hemerythrin: Some marine invertebrates and a few species of annelid use this iron containing non-heme protein to carry oxygen in their blood. Appears pink/violet when oxygenated, clear when not.
Vanabins: also known as Vanadium Chromagen are found in the blood of Sea squirt and are hypothesised to use the rare metal Vanadium as its oxygen binding prosthetic group, but this hypothesis is doubtful.
Erythrocruorin: found in many annelids, including earthworms. Giant free-floating blood protein, contains many dozens even hundreds of Iron heme containing protein subunits bound together into a single protein complex with a molecular masses greater than 3.5 million Daltons!
Pinnaglobin: Only seen in the mollusk Pinna squamosa. Brown manganese-based porphyrin protein.
Leghemoglobin: In leguminous plants, such as alfalfa or soybeans, the nitrogen fixing bacteria in the roots are protected from oxygen by this iron heme containing, oxygen binding protein.
Role in disease
Decreased levels of hemoglobin, with or without an absolute decrease of red blood cells, leads to symptoms of anemia. Anemia has many different causes, although iron deficiency and its resultant iron deficiency anemia are the most common causes in the Western world. As absence of iron decreases heme synthesis, red blood cells in iron deficiency anemia are hypochromic (lacking the red hemoglobin pigment) and microcytic (smaller than normal). Other anemias are rarer. In hemolysis (accelated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin.
Mutations in the globin chain are associated with the haemoglobinopathies, such as sickle-cell anemia and thalassemia.
There is a group of genetic disorders, known as the porphyrias that are characterized by errors in metabolic pathways of heme synthesis. King George III of the United Kingdom was probably the most famous porphyria sufferer.
Release of Hemoglobin into the blood, caused by lysing of red blood cells (for example like in Malaria) can damage the kidneys. Some sickle-cell anemics also suffer from kidney damage.
1A3N http://www.rcsb.org/pdb/cgi/explore.cgi?pid=205561034349094&page=0&pdbId=1A3N - PDB structure of human hemoglobin.
Last updated: 02-07-2005 06:29:56
Last updated: 05-03-2005 17:50:55