Seeing the Caffeine Molecule in Action

Did you ever wander what the caffeine molecule looks inside of us when it do all of its marvelous magic? I am not speaking here for the chemical structure of the molecule. This structure is very well known and you can see it in thousand pictures in internet or organic chemistry textbooks. I am speaking rather of seeing the caffeine molecule “in action” when it is doing all the wonderful job of tweaking our biological systems.
First I would like to start with a little bit background information. The caffeine molecule (left) resembles the cAMP molecule (right) or at least part of it (right upper part containing the blue balls (atoms)).
cAMP is something like a messenger within the cells – whenever certain hormone or neuromediator binds its receptor cAMP is synthesized and released within the cell. Than it binds different enzymes and influence their activity (usually the enzymes are activated). Because of its similarity caffeine molecule could bind the very same enzymes at the very same place where the cAMP is binding but contrary to cAMP the caffeine usually fails to activate the enzyme. It is interesting to know that one of this enzymes (called phosphodiesterase) is the very enzyme responsible for the degradation of cAMP. In that way by blocking the phosphodiesterase the caffeine can actually potentiate the action of cAMP.

The story is not so simple though. There is another enzyme which cAMP (and caffeine respectively) could bind. It is called Glycogen Phosphorylase A. This is an interesting enzyme as it is responsible for the utilization of glycogen in our bodies (glycogen is one of the important energy depots in our organism  – it is a very long molecule composed of chained (polymerized) glucose molecules). The Glycogen Phosphorylase A can add small molecule residuals (phosphates) to the glucose molecules of the glycogen. As a result other enzymes could detach easily the single glucose molecules and “send” them for the generation of energy. The binding of cAMP to Glycogen Phosphorylase A activates the enzyme whether the binding of caffeine molecule inhibits it. This is exactly and the place where the caffeine was “caught in action” by a research team in year 2002.

Ekstrom JL and colleagues used a special scientific method called crystallography. They co-incubated caffeine molecules with ultra pure Glycogen Phosphorylase A molecules. As a result the mixture crystallized (it is common for ultra pure mixture of protein molecules (and most of the enzyme are proteins) to crystallize under special conditions (not all protein molecules could form crystals though)). When you irradiate this crystals with X-rays you can generate a nice refraction pattern. Knowing the composition of the protein molecule (enzyme) (the exact sequence of amino acids), the refraction pattern and using some mathematics magic, one can generate a 3D model of the original molecule (enzyme). This is exactly what the research team did. As a result a nice picture of the Glycogen Phosphorylase A molecules bound to caffeine molecules was created:

Of course the colors of the image are not real (they are computer generated) but you could see clearly the small caffeine molecules bound to the two big subunits of the enzyme (violet and dark blue). The next image is a magnification of the green rectangle part of the previous one and it represents the binding place of one of the caffeine molecules (in yellow):

You can see how neatly the caffeine molecule positions itself in the grooves of the big enzyme molecule (the grooves are formed of the amino acid chains composing the enzyme). In doing that the caffeine molecules prevents the binding of cAMP to the very same site and as a result the enzyme is not activated. This property of the caffeine molecules is quite important as it could be used to potentiate the action of some anti-diabetic drugs (of course the caffeine has and many other actions also so in no way it could be used alone as a treatment of diabetes).

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