User:Jaime Prilusky/How do we get the oxygen we breathe

When we breathe, or respire, oxygen from the air is taken up by blood in our lungs and soon delivered to each of the cells in our body through our circulatory system. Among other uses, our cells use oxygen as the final electron acceptor in a process called aerobic respiration -- a process that converts the energy in food and nutrients into a form of energy that the cell can readily use (molecules of ATP, adenosine triphosphate). The cells of large organisms like humans use aerobic respiration because other forms of energy production are less efficient, and oxygen is plentiful. (THINK: Do fish use aerobic respiration?)

But, although oxygen is transported in our blood to reach each of the cells in our body, oxygen does not dissolve well in blood. So how is oxygen transported in the blood?

Hemoglobin, the oxygen taxi

A protein called (Hb), seen on the right, is the answer to the challenge of transporting oxygen in the blood. The many molecules of hemoglobin in our blood serve as “taxis” for oxygen molecules: oxygen molecules bind to hemoglobin molecules in areas where oxygen is plenty, such as in the lungs, and oxygen molecules then dissociate from hemoglobin when they reach oxygen-poor areas, such as near cells far from the lungs. In this way the hemoglobin in our blood traffics oxygen to every cell in our body. Hemoglobin needs to bind to oxygen tightly in the oxygen-rich atmosphere of the lungs and to be able to release oxygen rapidly in the relatively oxygen-poor environment of the tissues. It does this in a most elegant and intricately coordinated way. The story of hemoglobin is a prototypical example of the relationship between structure and function in a protein molecule.

The structure of hemoglobin

Hemoglobin is a tetramer

In the three-dimensional structure of hemoglobin to the right, you see two and two . (Drag the hemoglobin structure with the mouse to rotate it. To zoom, use your scroll-wheel, or drag while holding shift.) These are the of the hemoglobin molecule, and they are shown in a cartoon-style representation where a single curved line connects the α-carbons in the amino acids of each chain and the secondary structure α-helices are shown as simplified cartoon helices. Because hemoglobin is composed of four monomers, it is called a . The two types of monomers that make up the hemoglobin tetramer are distinguished by their color: the two α in light-blue and the two β in light-green. Each α-monomer is a chain of 141 amino acids and each β-monomer is a chain of 146 amino acids. Be careful not to get confused with the context in which we use the label "α", or "alpha": remember that both the α- and the β-monomers contain α-carbons and α-helices. (THINK: How many amino acids does it take to build a molecule of hemoglobin?)

Each monomer has a heme group

Notice that each monomer, whether α or β, has a associated with it that is represented by several multicolored, overlapping, small spheres. These molecules are called , and they are where oxygen binds to hemoglobin, which we will soon observe. Do the colors of the spheres represent the true colors of the heme group? No, they do not. Remember that we are looking at a representation of the real structure, and in this case we have artificially colored each atom in the heme according to a common color scheme called the Corey-Pauling-Koltun scheme ( C

H O N S Fe ). Remember too that although we cannot change the positions of the atoms in our experimentally determined protein structure, we can freely choose different ways to show, color, and connect these atoms in order to best comprehend and convey the niceties of the complex 3D structure. We have previously represented the atoms of the heme group as individual spheres in what is called a , but we could just as easily represent the atoms as very small spheres with thick lines connecting the bonded atoms in what is called a . Notice that the positions and identities of the atoms do not change. (THINK: Earlier we learned that the α- and β-monomers have so far been shown in cartoon representation. Why can’t we show the heme groups in cartoon representation?)

Capturing oxygen

Hemoglobin captures oxygen and transports it through the bloodstream by binding oxygen to each of its *four heme groups*. These *heme groups* are prosthetic groups; they are non-protein chemical compounds that are associated with hemoglobin and are necessary for its function. Each heme is a ring molecule made up of Carbon, Nitrogen, Oxygen and hydrogen, with a single Fe²⁺ (iron) ion at its center, coordinated by the four surrounding nitrogens. Each heme is roughly *planar*, and is held in place within the monomer by a hydrophobic interactions and a *covalent bond * between the iron ion and a nitrogen atom in the side chain of what is termed the proximal histidine. Another histidine, termed the *distal histidine*, helps in oxygen binding by prevents oxidation of the iron atom (which would prevent oxygen from binding) and by preventing other molecules from binding.

When oxygen is abundant, an in the heme group. (‘‘OBSERVE’’: Are there other changes besides the oxygen binding to the iron ion?) We can watch oxygen binding in the or in a of the heme group.

When oxygen binds the heme, we notice a conformation change in the hemoglobin monomer holding the heme that bound oxygen -- in other words, when oxygen binds, the monomer changes shape. The difference in conformation between the oxygenated and deoxygenated monomer turns out to be crucial for the function of hemoglobin. Remember that hemoglobin does not exist as a monomer, but rather as a tetramer. As a result, when one monomer in a deoxygenated hemoglobin molecule binds oxygen, that monomer’s conformation change forces a similar conformation change in the remaining three monomers, causing them to adopt a conformation more favorable to oxygen binding. Said differently, as soon as one monomer in the tetramer of the hemoglobin molecule binds oxygen, the other three monomers are much more likely to bind oxygen than they were before. This mechanism of accelerated binding through monomer conformation propagation is called cooperative binding.

Carbon monoxide also binds the heme

Here is where the laws of chemistry present us with an interesting problem: The heme group has the chemical and structural capabilities to capture an , but an oxygen molecule (O₂) happens to be similar in shape and chemistry to a molecule of (CO). The result is that carbon monoxide can also bind to the iron in the heme groups of hemoglobin. In fact, carbon monoxide binds to the heme with about 230 times the affinity of oxygen, meaning that if both gases are available, carbon monoxide will outcompete oxygen for heme binding sites. (THINK: We often install carbon monoxide detectors in our homes to alert us to high concentrations of this gas. Why might carbon monoxide gas pose a danger to human beings?)

Mutated hemoglobin causes sickle-cell disease

differs from normal hemoglobin by a single amino acid: valine (hydrophobic) replaces glutamate (hydrophilic) at position 6 on the surface of the beta chain. This creates an hydrophobic spot. THINK: Why a simple additional hydrophobic spot (actually two spots in the structure WHY?), generated by the change of a single amino acid on a protein with over 500 amino acids becomes so problematic?

On the right, we can see the structure of a deoxygenated hemoglobin, this is, an hemoglobin shortly after releasing the load of oxygen. We can distinguish it's four chains (by it's artificial colors) and the four heme groups with no oxygen attached. This time, the representation is of style spacefill, which is Ok because you know by now that representations are only a different way of drawing a real structure that we can't see.

Both normal and sickle hemoglobin, when in deoxygenated state, have an

(colored white here) on the beta chains. Two beta chains = two hydrophobic spots on the dehydrogenated hemoglobin. WATCH: Can you find the spots on the two chains?.

The present on Sickle hemoglobin sticks to the hydrophobic spot present on dehydrogenized hemoglobin, causing hemoglobin molecules to

into chains forming long fibers. this scene shows just two hemoglobin molecules stuck together, but this chain can extend to include many many hemoglobin molecules. A shows us that Alanine and Leucine from one molecule attract the Valine from another, chaining the two hemoglobin molecules together.

External ResourcesExternal Resources

Hemoglobin in Wikipedia

Hemoglobin Causes Net Diffusion of Oxygen (Interactive Demo) - Oxygen diffuses freely across oxygen-permeable membranes such as those found where capillaries (small blood vessels) in the lungs make contact with the air we breathe. When oxygen diffuses from the air in our lungs across the walls of these capillaries and into our blood, it is taken up by hemoglobin -- this causes even more oxygen to diffuse into the blood in order to balance the concentration (partial pressure) of free oxygen in our blood with that in the air in our lungs. Explore the interactive demonstration to see this diffusion in action.

Content ContributorsContent Contributors

This page includes scenes, structures and ideas from Eric Martz, Frieda S. Reichsman and Angel Herraez.