Magnificent Conotoxins – Expanded

“… if a small and otherwise unknown organism is strikingly beautiful, it is probably poisonous; if it is not only beautiful, but also easy to catch, it is probably deadly.”

-Edward O.Wilson in:
THE FUTURE OF LIFE
Vintage Books, March 2003

The realm of proteins

Proteins are probably the most versatile molecules within a living cell. They can form literally thousands of different structures which perform all the physiological processes that generate the phenomenon of life. Some of the many different structures that are made by proteins include enzymes, which are molecules that speed up biochemical reactions, structures like the microtubules, involved in cell division and cell shape and even the antibodies in our immune system, responsible of defending us against harmful exogenous agents. These are only examples of the unique versatility of proteins; we just barely scratched the surface.

Proteins are polymers; a polymer is a chemical entity formed by smaller subunits, called monomers, organized very much like the links in a chain. The individual links represent the monomers and the chain itself represents the polymer.

The monomers that form proteins are called amino acids. There are hundreds of amino acids found in nature. Remarkably, life as we know it uses a limited set of twenty amino acids, which are specified by the genetic code. With very few exceptions, life, from the smallest bacteria all the way to the blue whale, uses the exact same 20 amino acids!

How do amino acids make proteins? To understand this, we need to take a little detour into the realm of structural biology.

Amino acids are organic molecules. This means that at their very core, there are carbon atoms. Nineteen of the twenty amino acids (from now on, “AA” for short) have exactly the same basic structure:


General amino acid structure

The trick to make all these different proteins that are specific to an organism is the type of amino acids and the precise order in which they are arranged. Moreover, most amino acids are chiral, which means that they can appear in two basic versions, L or D (look it up); life only uses the L-type.

The “R” group is the variable part of an AA; it is what determines the specific chemical properties of a given AA, for example, charged vs. non-charged, polar vs. non polar, etc. Chemically speaking, amino acids react with other amino acids through their amino and carboxyl groups to form a special kind of bond called the peptide bond, as shown below.


Representative peptide bond and polypeptide. When peptide bonds are formed, a water molecule is liberated; therefore this reaction is sometimes classified as a condensation reaction.

The type of amino acids in a protein largely determines the protein final structure and thus its function. However, the order of the amino acids is also important. In other words, a short protein formed by AAs 1-2-3-4 is not the same as another protein containing the same AAs ordered as 4-1-3-2, or any of all the other possible combinations. Some proteins are composed by thousands of amino acids; this will give you an idea of the many different kinds of possible structures. A point of nomenclature: when a protein is formed by up to 30 amino acids or so, it is usually called a polypeptide or peptide for short.

Conotoxins

Toxins and venoms are some of the most fascinating substances present in living organisms. In general, toxin and venom components are used as the means for an organism to defend itself or to kill other organisms for nourishment.

Even though the terms “toxin” and “venom” are often used interchangeably, there are important differences between the two. Venoms usually consist of a complex combination of many different toxic substances (toxins), which can be small organic molecules, peptides or even large proteins. In general, a venomous organism possesses anatomical structures to store the venom and a mechanism to deliver it, usually in injectable form; think about fangs, like some snakes, spiders, etc.

Some of the most interesting venomous organisms are certain types of marine snails, the cone snails. This is a relative recent class of snails, as they seem to have evolved about 50 million years ago. They are widely distributed in marine environments, with species found in every major ocean. Many species of these molluscs are brightly colored and are therefore highly prized by serious shell collectors.

image

http://nihrecord.nih.gov


Conus amadis. This cone snail species hunts other snails (©Baldscientist)

All species of cone snails are predators. Some cone snails hunt marine worms, several species hunt other snails and yet some other species feed exclusively on fish.

Yes, fish.

Did I mention that cone snails are, well, snails?

Snails are invariably S-L-O-W. Cone snails are no exception. How are these organisms capable of hunting fish?

Cone snails have evolved a series of very potent venoms, with toxin components targeting several aspects of neurotransmission, namely various types of ion channels. These toxins produced by cone snails are generally called conotoxins. These are short peptides, usually no more than 20 AA long. When a cone snail is hunting, it extends a proboscis (different from the one I mentioned here) which has at the tip a harpoon-like structure (below) through which the venom is injected.

When a fish is stung, the several types of conotoxins present in the venom simultaneously block several types of molecules important for the proper function of their nervous system. This happens very fast, the fish is paralyzed within two seconds or so! If you think about it, this makes perfect sense, since if the venom were not that fast-acting, the fish would be able to swim away before becoming paralyzed. By the time the snail gets to the fish, it would have probably been already eaten by something else and therefore the poor cone snail would go hungry. For a cone snail-related page with useful information, click here.

The story of how conotoxins were discovered starts in the 1700s, when the first reports of fatalities associated with cone snail handling were firstly described. The dangerous nature of many species of cone snails was very well known; there are well-documented cases of human fatalities caused by cone snail stings. In the late 1950s the first reports of fish-hunting snails were published. In the 1970s, there were early attempts to isolate and characterize some of their venom’s components.

The “modern” era of conotoxin research began with the work of Dr. Baldomero Olivera, of the University of Utah, USA. Many different types of conotoxins were isolated and characterized in his laboratory. Since then, other research groups have “joined the hunt” to help study this promising class of pharmacological agents.

Conotoxins have proven invaluable to study many of the components of the physical point of contact between nerve cells and nerve cells and between nerve cells and muscle. These component include neurotransmitter receptors and transporters. Briefly, there are receptors for a wide variety of chemicals in nervous systems; these molecules control cell-to-cell communication. Many of these chemicals include molecules such as neurotransmitters. Clinically, neurotransmitters play a role on pathological conditions as varied as anxiety and depression, as well as neuromuscular and cardiovascular disorders among many others. Neurotransmitter receptors also play a role in anesthesia for example. There are thousands of these types in a typical organism.

Remarkably, there seem to be conotoxin types that target virtually every class of neurotransmitter receptor known (actually, as far as I know, there is only ONE exception, more on that later on…). Biochemically, we say conotoxins display selectivity towards some receptors and not others. In fact, some conotoxins are so selective that they are able to distinguish between regions in the same receptor! This is really close to my heart, as it was the topic of the first two scientific papers of which I was a coauthor:

The alpha-conotoxins GI and MI distinguish between the nicotinic acetylcholine receptor agonist sites while SI does not. Hann RM, Pagán OR, Eterović VA. Biochemistry. 1994 Nov 29;33(47):14058-63.

(This year is the 20th anniversary of this paper!)

And

The 9-arginine residue of alpha-conotoxin GI is responsible for its selective high affinity for the alphagamma agonist site on the electric organ acetylcholine receptor. Hann RM, Pagán OR, Gregory LM, Jácome T, Eterović VA. Biochemistry. 1997 Jul 22;36(29):9051-6.

The two papers above are on the same neurotransmitter receptor that I talk about here.

Fundamental research is fun, but what about its practical importance? In other words, why would we spend time, efforts and money to study conotoxins?

Well, in at least one case, a cone snail toxin has proven to be useful in human medicine. Ziconotide (Prialt®) is the synthetic version of a conotoxin that blocks a particular ion channel important in neurotransmission. This medication has been approved and is currently used in cancer patients suffering with otherwise intractable pain.

This example is a very direct illustration of the importance of biomedical research. Who would have thought that by studying a marine snail you could alleviate the suffering of a cancer patient?

Ziconotide is only one example of a cone snail compound. It is estimated that there are about 700 species of cone snails, each of those with up to 200 different venom components. That translates to about 140,000 possible compounds! Conotoxins are being looked at for the development of analgesics, antiepileptics and even as anticancer compounds.

How many cone snail compounds are waiting to be discovered? What would be the next useful drug derived from them?

Here are two review (and free) papers that explore aspects of the potential of conotoxins to develop new medications:

Strategies for the development of conotoxins as new therapeutic leads. Brady RM, Baell JB, Norton RS.
Mar Drugs. 2013 Jun 28;11(7):2293-313.

And

Conotoxins that confer therapeutic possibilities.
Essack M, Bajic VB, Archer JA.
Mar Drugs. 2012 Jun;10(6):1244-65.

Now, remember a few lines back about the only neurotransmitter receptor that does not have a conotoxin associated with it (so far)? This receptor class is the GABA-A receptors (why are they named like that is not important right now). These receptors control a series of events that decrease the activity of neurons, as opposed to activate them. This property has been extensively taken advantage of to develop antianxiety medications. If you have even taken drugs like Ativan, Xanax, Valium, etc., you know what I am talking about.

Why does it seem that there are no conotoxins selective for GABA-A receptors? Usually, when there is an apparent “gap” in nature such as this it means that an important principle is waiting to be discovered. I, for one, will stay tuned.

As a good friend have said, science is stranger than fiction.

If you want to know more

Olivera BM, Cruz L (2001) Conotoxins in retrospect. Toxicon 39:7:14.

Styx G (2005) A toxin against pain. Scientific American, March.

Tanford, C, Reynolds, J (2004) Nature’s Robots: A History of Proteins Oxford University Press, USA; 1st edition

~~~

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TFB is available as an ebook (Kindle, Nook, as well as in iTunes). The hardcover is available at Amazon and at the Oxford University Press’ website.  There’s even a 20% discount code from OUP.  Shoot me a message if you have any questions!

 

 

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10 Comments

  1. We have been visited by baby skunks which made me wonder if anyone has studied skunk spray for potential beneficial applications.

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