Hemoglobin

From Academic Kids

3-dimensional structure of hemoglobin
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3-dimensional structure of hemoglobin

Hemoglobin or haemoglobin 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.

Contents

Structure

Heme group
Heme group
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. The iron atom binds equally to all four nitrogens in the center of the ring which lie in one plane. Two additional bonds perpendicular to the plane on each side can be formed with the iron to form the fith and sixth positions. The iron atom can either be in Fe+2 state or Fe+3 but ferrihemoglobin (Methemoglobin) (Fe3+) cannot bind oxygen. 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 and hemoglobins. All hemoglobins contain either two α or two ξ chains. Hemoglobin A is by far the best known.

In adult humans, the most common hemoglobin is a tetramer (contains 4 subunit proteins) called hemoglobin A, consisting of two α and two β 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:

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

Quaternary structure

The four polypeptide chains are bound by hydrogen bonds, salt bridges, and hydrophobic bonds. There are two kinds of contacts between the α and β chains: α1β1 and α1β2. The contacts tend to be hydrophobic but are important in the allosteric interactions.

Types of hemoglobins

Embryonic hemoglobins:

  • Gower 1 (ξ2ε2)
  • Gower 2 (α2ε2)
  • Hemoglobin Portland (ξ2γ2)

Adult hemoglobins (this does not mean that these hemoglobins are not created during fetal development but rather these hemoglobins still persist into adult life):

  • Hemoglobin F2γ2) - In adults Hemoglobin F is restricted to a limited population of red cells called F cells.
  • Hemoglobin A (α2β2)
  • Hemaglobin A22δ2) - δ chain synthesis begins late in the third trimester and in adults, it has a normal level of 2.5%

Binding of ligands

Missing image
Hemoglobin_t-r_state_ani.gif
Steric conformations of hemoglobin in oxy and deoxy forms.

In the tetrameric form of normal adult hemoglobin, the binding of oxygen is a cooperative process. The binding affinity of hemoglobin for oxygen is increased 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 monoxide because both gases compete for the same binding sites on hemoglobin, carbon monoxide binding preferentially to oxygen. Carbon dioxide occupies a different binding site on the hemoglobin. Carbon dioxide reacts with water to give bicarbonate, carbonic acid freed protons via the reaction, which is catylised by carbonic anhydrase:

CO2 + H2O <-> HCO3- + H+
Missing image
Hb_saturation_curve.png
Hemoglobin sigmoidal oxygen dissociation curve

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 than its affinity for oxygen, meaning that small amounts of CO dramatically reduces hemoglobins ability to transport oxygen. When hemoglobin combines with CO, it forms a very bright red compound called carboxyhemoglobin. When inspired air contains CO levels as low as 0.02% headache and nasuea occur; if the CO concentration is increased to 0.1%, unconsciouness will follow. In heavy smokers, up to 20% of the oxygen active sites can be blocked by CO.

Hemoglobin also has competitive binding affinity for Sulfur monoxide (SO), Nitrogen Dioxide (NO2) and Hydrogen sulfide (SH2). The iron atom in the heme group must be in the Fe+2 oxidation state to support oxygen transport. Oxidation to Fe+3 state converts hemoglobin into hemiglobin or methemoglobin which cannot bind oxygen. Nitrogen Dioxide and Nitrogen_monoxide are capable of converting hemoglobin to methemoglobin.

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 hemoglobin

When red cells reach the end of their life, they are broken down, and the hemoglobin 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 degraded 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. Other organisms including bacteria, protozoans and fungi all have hemoglobin like proteins, their known and predicted roles include the reversible binding of gaseous ligands.

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, it is a monomer and lacks cooperative binding and is used to store oxygen rather than 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 unconfirmed.

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 (accelerated breakdown of red blood cells), associated jaundice is caused by the hemoglobin metabolite bilirubin, and the circulating hemoglobin can cause renal failure.

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.

Diagnostic use

Hemoglobin levels are amongst the most commonly performed blood tests, usually as part of a full blood count. Results are reported in g/L, g/dl or mmol/L. For conversion, 1 g/dl is 0.62 mmol/l.

See also

External links

  • 1A3N (http://www.rcsb.org/pdb/cgi/explore.cgi?pid=205561034349094&page=0&pdbId=1A3N) - PDB structure of human hemoglobin.da:Hmoglobin

de:Hmoglobin es:Hemoglobina eo:Hemoglobino fr:Hmoglobine id:Hemoglobin ia:Hemoglobina it:Emoglobina he:המוגלובין ms:Hemoglobin nl:Hemoglobine ja:ヘモグロビン pl:Hemoglobina pt:Hemoglobina fi:Hemoglobiini zh:血红蛋白

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