The Magnificent Conotoxins

“… 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

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 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.


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.

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, albeit in an anecdotical way. 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.

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!

How many cone snail compounds are waiting to be discovered? What would be the next useful drug derived from them? 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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7 Comments

  1. Love the opening quote, makes perfect sense in light of evolution.

    With over a hundred amino acids found in nature but only twenty specified by genetic code, with a few tantalising exceptions, I wonder if this is a bit of a fingerprint, revealing a little about the nature of abiogenesis.

    http://www.abc.net.au/science/articles/2012/02/27/3440345.htm

    I like the example of Ziconotide. Given the vast number of possible peptides that can be formed, it makes sense to look at what Natural Selection has determined as a viable combination over hundreds of millions of years rather than trial and error in the lab (although that can yield results too). Nature provides us with a short-cut in understanding what can be achieved. Taxotere is a chemotherapy drug extracted from the bark of the Yew tree, while venom from the copperhead snake is being used to treat breast cancer. We may yet see conotoxins used as well.

    Great article

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