Crazy medicine

Both Doug and I enjoyed John Burdett's recent Asian thriller Bangkok 8, set guess where. (It has weird sex, snakes. and revenge! What more do you need?) Anyway, one of the subplots in the book deals with the Asian amphetamine trade. This is not a matter of guys with bad teeth setting up trailers in the middle of nowhere. Well, OK, it is, but instead of manufacturing the crank from scratch, in Asia they extract a precursor from local Ephedra shrubs first. Which brings me to the real point of this post, phytochemistry! The Ephedra are weird-looking shrubs, sometimes called the joint-firs in English. You can see why. Ephedra itself is a living fossil, one of only three (maybe four) surviving genera of the gnetophytes, until recently thought to be the closest living relatives of the flowering plants. Ephedra have been found from the Cretaceous period, over 65 million years ago. They also have a remarkably odd biochemistry: they produce cyclopropyl amino acids. This may require some explanation.

Amino acids are the building blocks of all proteins. There are twenty principal amino acids, which you can find mention of in all the textbooks, and a whole bunch more of modified ones, for which you have to dig around a little more. Now, a protein is a polymer, like a plastic. Every protein molecule consists of chains of amino acids stuck together, like Legos. How do they manage this? Every amino acid has an acidic end and a basic end. During protein synthesis, the acidic end of one amino acid is made to react with the basic end on another, and voila! a bond is formed, and the protein increases in length by one more amino acid. Sounds complicated? It is. But it's a precise and accurate and surprisingly robust system. However, there are certain points where it can be jammed. Somewhere along the line, Ephedra evolved the ability to synthesize amino acids that contain carbon rings with only three atoms: cyclopropyl groups. This is weird, because this stresses the chemical geometry of the carbon atom almost to its limit. It's not particularly easy for organic chemists to do. And Ephedra does this on a bulk basis. It appears that Ephedra has evolved this as a form of chemical defense. Large amounts of these variant cyclopropyl amino acids are produced, up to 0.5% of the plant's dry mass. These amino acids are taken up by organisms that use the plant as food. But these variant amino acids, similar in affinity but crazily different in structure to everyday amino acids, gum up the parasite/herbivore's amino acid metabolism, in effect poisoning them in the midst of plenty. They die. Oh the embarrassment. (In fact, one species of Ephedra is called Ephedra antisyphilitica, although its anti-spirochete action has never been confirmed.) Except that's not all. Because evolution reuses its biochemistry, it turns out that the common amino acid glutamic acid (or glutamate, same as in MSG) is also a neurotransmitter. Would it surprise you that Ephedra also synthesizes cyclopropyl analogs to glutamate? While they jam up very specific glutamate receptors in vitro, the neurological effects of these chemicals on humans are unknown. As a completely separate matter, some species of Old World Ephedra also can also be up to 2% its dry mass in ephedrine or pseudoephedrine, compounds chemically very similar to methamphetamine. Hence their use as starting material in illegal synthesis. However, in New World Ephedra, those compounds are barely detectable in the plant, thus the different style of trailer labs alluded to above. However (again), a common name for North American Ephedra is "Mormon tea" [1], which suggests some sort of stimulant action is going on, which brings us back to the unknown neurological effects I mentioned before. Finally, going back to my previous post on paleoecology, the gnetophytes were once much more common than they are now. The genus Ephedra itself dates back to the Cretaceous. It seems likely that its peculiar biochemistry dates back that far as well. What I'd like to know is, what were the selective pressures which caused Ephedra to evolve this complicated biochemistry in the first place? Or, to put it another way, was Ephedra originally dinosaur crank? [1] This may require some explanation for those three eastern European readers who have read this far. The Mormons are a religous group, mainly found in the American West, who abstain from all caffeinated beverages!!! Apparently, some of them were willing to drink tea made from a living fossil instead. Many Mormons also believe in something much like the first series of Battlestar Galactica, but with Jewish American Indians taking the place of Lorne Greene and killer robots. I don't say it's related to their abstention. I don't say that at all.

Comments

[Doug M.]

Why three-rings, I wonder. IMS (and it may not) there are four- and five-rings too: easier to synthesize, and ought to screw up the herbivore's chemistry just as well.

Ginkgoes -- another very old plant family with just a few modern representatives -- also produce some very strange compounds. Makes you wonder what a Cretaceous pharmocopeia would have looked like.

Also if plant life has gotten better, worse, or about the same in terms of synthesizing weird stuff. No way to ever know that, of course. (Though I can come up with a Just So Story: dinosaurs, huge and hard-mouthed, ignored mechanical defenses like thorns. So plants were forced to come up with ever more bizarre and brilliant chemicals.)

Doug M.

[Carlos]

Doug, the three-membered rings are in very specific places. There seem to be two main types of cyclopropyl variants, ones that mimic the amino acid proline, and ones that mimic the amino acid glutamic acid.

In the proline analogs, the cyclopropane ring actually shares an edge with the five-membered ring which makes up the proline molecule's "backbone". Proline is the only amino acid to incorporate a ring in its backbone, and because of the rigidity this introduces to proteins, it's widely used when the protein needs to make a sharp bend. Collagen, in fact, is about one-third proline, because it winds in the opposite direction of most proteins, left-handed versus right-handed.

The variant proline seems to completely disrupt proline intake and metabolism. The extra carbon on the side causes the molecule to bind better to enzymes which normally bind proline than proline itself.

The cyclopropyl glutamate variants work in a somewhat different way. Glutamate is an amino acid, but it also has an extra acidic group on its "side chain". In shape, but not in charge, the cyclopropyl group is a relatively close mimic of this acidic group. So for the enzymes and receptors that don't use the acidic properties of the glutamate side chain when they bind to a molecule, the cyclopropyl variants are excellent mimics.

In neither case would four-membered (or larger) ring variants be useful.

(Which is not to say that strained rings are not biologically useful, because they are. The strained beta-lactam four-membered ring in penicillin is what gets the job done.)

There are other plants which produce the proline variants -- the horse chestnut, for instance -- but very few seem to produce the glutamate variants.

The go-to paper for this is Caveney et al., "New observations on the secondary chemistry of world Ephedra (Ephedraceae)", American Journal of Botany 88(7): 1199–1208. 2001.

[Graeme]

Interesting.

Also, the Wikipedia page on Ephedra, which I found from your gnetophytes link above, has this line: "The Chinese name is , ma huang, which means "yellow hemp"". I assume for the medicinal properties, since it doesn't seem to look much like hemp.

[Carlos]

This is a slight nitpick, but "ma huang" actually means "hemp yellow" or "numbing yellow". There's no word order inversion as in English in classical Chinese, and the word for hemp has both nominal and verbal qualities.

It might have had a similar meaning to what English-speakers would call "yellow hemp" -- probably does, in my amateur opinion -- but it might not've.

[Syd Webb]

Carlos,

I showed this piece to Beatrix. It appealled to her on so many levels. She spent the next half-hour Googling a variety of sites offering varying perspectives on 'Mormon tea.'