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If you bite it and you die, it’s poisonous. If it bites you and you die, it’s venomous.
@SciencePorn Feb 4, 2014
Medicines from toxins 1: Statins
In a previous post I talked a little bit about nature’s chemical weapons and briefly explored the wide variety of chemical structures that nature has to offer in this context, substances whose main “purpose” (I’m just personifying) is to actually help the organism that produces it to capture prey or to avoid becoming prey.
That being said, just in the same way that a knife can be used as a tool or as a weapon, many such toxic molecules have found their way to your medicine cabinet.
Yep, your medicine cabinet.
You see, many toxins work by inhibiting (a fancy way to say ‘blocking’) key proteins that control a wide variety of chemical reactions within organisms. This fact, combined with another fact, namely that all life on Earth is related, means that many of the main biochemical pathways crucial for life will be shared by most, if not all organisms. These biochemical pathways are controlled by specialized proteins called enzymes.
Enzymes include some of the most interesting types of molecules around. They are largely responsible for all the multiple chemical reactions that are necessary for an organism to stay alive. But, what exactly is it what they do? Essentially, they facilitate (the technical term is catalyze) chemical reactions that oftentimes require an extreme condition to happen, for example, pressure, pH, high temperature etc. By the way, not all enzymes are proteins, certain types of nucleic acids are also able to catalyze biochemical reactions; we may talk about them some other time.
Let’s suppose that the “chemical reaction” that needs to happen is the detachment of a key from the key ring. Left to itself, the key **will** come off the metal ring, maybe after hundreds of years when the metal ring or even the key itself rusts and disintegrates. We can also make this happen with an acetylene torch to melt the ring or we can use acid to dissolve the metal, among other “extreme” strategies.
I can use my fingers to gently slide the key off the ring.
That is what enzymes do. They provide the appropriate conditions to make a certain chemical reaction happen without the need of anything extreme like long time, high temperature or corroding acid. In chemical parlance, they lower the energy of activation of a given chemical reaction. Meaning, again, that a given chemical reaction will not need as much energy to be carried forward. This is a pretty handy ability for organisms that live in rather mild conditions (external and internal), ourselves included. Briefly, the specific chemical entity that an enzyme works on is called the substrate and whatever results from it is called the product.
All organisms possess many enzymes that work in complex ways to perform a particular function. In many instances a group of enzymes work together in such a way that the product of one reaction is the substrate of the next and so forth.
However, some reactions are more critical than others, albeit in an unexpected way. For example, in a set of enzymes, the speed of catalysis differs from enzyme to enzyme. Usually one of these steps is the “slowest” one; that step largely determines the overall “speed” of the complete enzymatic pathway. That specific step is the “rate-limiting step”. Not surprisingly, quite a few enzymatic systems and especially their rate-limiting steps are pharmacological targets, like the enzymes responsible for the synthesis of a quite misunderstood molecule: cholesterol.
You may be surprised to learn that cholesterol is actually an important molecule in all types of organisms, not just animals (plants have it too; I bet you didn’t know that!). In animals, this compound is the precursor of many hormones like estrogen and testosterone as well as cortisol, one of the so-called “stress hormones”. As with many things in life though, excesses are bad. In particular, too much cholesterol is not a good thing and this excess is undeniably related to cardiovascular disease. Biochemically, a common pathway for cholesterol biosynthesis is composed of a series of steps catalyzed by a variety of enzymes. This set of reactions start with a molecule called HMG-CoA.
In the 1960s Dr. Akira Endo joined later by Dr. Masao Kuroda, explored the hypothesis that fungi and bacteria may produce compounds capable of inhibiting the biosynthesis of cholesterol. The history of this chapter on the history of medicine is fascinating, and at the end of this post I have listed useful further readings. To make the long story short, they isolated a compound from the mold Penicillium citrinum a compound capable of blocking the enzyme responsible for the rate-limiting step on cholesterol synthesis, namely the conversion of HMG-CoA to mevalonic acid (the enzyme HMG CoA reductase; see figure above). They called this substance “mevastatin” which roughly means “stops mevalonic acid” from being synthesized, that is. The main consequence of this is to stop the series of chemical reactions that end in cholesterol. Since then, several other compounds, now collectively called “statins” are part of the tools that we have to try to manage medical conditions related to high cholesterol levels.
Adapted from Tobert (2003)
I hope that you agree with me when I say that the history of statins is an ideal illustration of the importance of fundamental research. It is remarkable how a family of molecules that are used by an organism as a chemical weapon found its way to a type of medications that has undoubtedly saved quite a few lives. And that came about from the study of “lowly” fungi. There are many examples of medication that had their origins in the natural world but I have a feeling that we have merely scratched the surface of this rich resource. I cannot help but wonder how many more molecules with properties that we can use for our benefit are waiting to be discovered. Interesting times ahead!
If you want to know more
Behrman EJ, Gopalan V (2005) Cholesterol and plants. J. Chem. Educ. 82,1791–1793.
Endo A (1992) The discovery and development of HMG-CoA reductase inhibitors. J Lipid Res. 33(11):1569-82.
Li JJ (2006) Laughing Gas, Viagra, and Lipitor: The Human Stories behind the Drugs We Use. Oxford University Press.
Rea PA (2008) Statins: from fungus to pharma. Am. Sci., 96: 408-415.
Tobert JA (2003) Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov. 2(7):517-26.