Hemoglobin

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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 molecule.

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.

Table of contents

1 Structure
2 Binding of ligands
3 Degradation of haemoglobin
4 Similar proteins
5 Role in disease
6 See also
7 External links

Structure

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 and globin, 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, 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, for a total molecular weight in the tetramer of about 64,000. Each subunit of hemoglobin contains a single heme, so that the overall binding capacity of adult human hemoglobin for oxygen is four oxygen molecules:

Stepwise Reaction:

Hb + O₂ <-> HbO₂
HbO₂ + O₂ <-> Hb(O₂)₂
Hb(O₂)₂ + O₂ <-> Hb(O₂)₃
Hb(O₂)₃ + O₂ <-> Hb(O₂)₄

Summary Reaction:

Hb + 4O₂ -> Hb(O₂)₄

Binding of ligands

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is a cooperative process, due to allosteric regulation. The binding affinity of hemoglobin for oxygen is affected 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.

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, 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 a 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 as well is affected by molecules such as carbon monoxide (e.g. from tobacco smoking) or 2,3-diphosphoglycerate, which lowers the affinity of hemoglobin for oxygen.

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 H, 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.

Similar proteins

Finally, it should be noted that hemoglobin is by no means unique. There are a variety of oxygen transport proteins throughout the animal (and plant) kingdom. Muscle tissue contains the hemoglobin-like pigment myoglobin. Some marine invertebrates and one species of annelid use an iron containing non-heme protein called a hemerythrin. Many annelids, including the earthworm, use an oxygen transport protein called an erythrocruorin. Many arthropods and molluscs use a class of compounds, the hemocyanins, that contain copper instead of iron. And in leguminous plants, such as alfalfa, the nitrogen fixing bacteria of the roots are protected by leghemoglobin, a protein synthesized by the combined action of plant and bacterium.

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.

Mutations in the globin chain are associated with the haemoglobinopathies, such as sickle-cell anemia and thalassemia.

There is a 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.

External links

1A3N - PDB structure of human hemoglobin.