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See Inside Scientific American Volume 308, Issue 5

Nature Is Not Ambidextrous




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Why Nature favors making left-handed proteins and right-handed carbohydrates is one of the great mysteries of life, as Sarah Everts explains in the May issue of Scientific American. By contrast, the manufacturing processes used by pharmaceutical companies are far less discriminating—typically producing right- and left-handed versions of the desired compounds in equal numbers.

Such molecules are mirror images of each other. Each version consists of the same component atoms arranged in the same order, but the two versions, referred to as enantiomers by scientists, cannot be superimposed on each other. Similarly, if you look at your right and left hand, you can see that—barring accident—they are mirror images of each other but you cannot lay one on top of the other and have the fingers match up.  

For many years, researchers assumed that mixtures of enantiomers wouldn’t make much of a practical difference when it came to making medicines. The body would respond to the appropriate mirror molecule and ignore the other compound. Unfortunately, for a variety of complex chemical and biological reasons, that has turned out not to be the case. In some instances, for example, what you would normally expect to be the inactive enantiomer ends up being toxic instead. Or the body will convert even pure quantities of one enantiomer into a mixture of both versions.

The exact details can be quite difficult to decipher. When scientists were trying to figure out why the sleeping pill known as thalidomide caused birth defects in the early 1960s, they first focused on the fact that the drug comes in a right-handed form and a left-handed form. Studies conducted in mice and rats in the late 1970s concluded that the left-handed enantiomer was responsible for birth defects while the right-handed version acted as a sedative. So thalidomide would have been safe in people, so the thinking went, had it consisted of only the right-handed molecule.

But that conclusion turned out to be too hasty. Studies on rabbits, which are more closely related to humans than rodents, showed that both enantiomers could cause birth defects. Furthermore, experiments in the 1990s showed that even pure preparations of right-handed thalidomide into mixtures of right- and left-handed molecules in the human body. So not only could you be making a deadly mistake in thinking that the right-handed version of thalidomide is safe, it doesn’t even matter whether or not it is because once in the body at least some of the right-handed enantiomer will quickly turn into the left-handed form, which is known to be unsafe.

Just to make matters even more complicated, sometimes a mix of right-handed and left-handed enantiomers of the same molecule is safer and more effective as a drug than a “pure” version of either mirror image because the two forms keep each other—and their disparate side effectives—in check.
 
If all this organic chemistry is triggering nightmarish flashbacks, listen in as Jad Abumrad and Robert Krulwich reflect on the lighter side of Nature’s handiwork (get it?) in this podcast

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