Papaver somniferum capsule exuding latex. Source of morphine, codeine and other benzylisoquinoline alkaloids.
Well today’s presentation certainly went well! Little fast compared to my rehearsals at home, but nothing unreasonable. The comments I had after I finished were quite positive, and the best part was we had a great discussion after about the concepts I presented . So all-in-all I suppose you could say I put up a “W” today. Wooot!
This was the last, mandatory oral presentation for my PhD thesis seminar. For this seminar I choose to talk about plant specialized metabolism, and the theories scientists use when they explain the vast chemical diversity in nature, and specifically plant systems. I’ll summarize my talk in this blog post. It may end up being lengthy, but I’ll keep the content accessible to everyone, and I hope you’ll find it worth while. Maybe we can get a spirited discussion here just like I had in class.
Plants are incapable of moving about and interacting with their environments like animals, insects and bacteria. Nevertheless plants must perform similar biological functions that these other organisms do, all while maintaining the same geographical location. For example; plants must defend themselves against herbivory and infection. They must communicate with each other, with animals and with insects. It’s necessary, at times, for plants to form symbiotic relationships with bacteria to access limiting environmental nutrients. Not surprisingly plants must also compete with other plants for terrain, light, water and other resources. Specialized metabolites, historically referred to as secondary metabolites, are small molecules synthesized by plants to perform these biological functions. As you can imagine the structural diversity of plant specialized metabolites is as diverse as their activities.
Specialized metabolites are not only important to plants. Human society has exploited these chemical entities for thousands of years as well. Our food, spice, fragrance, cosmetic and medical industries are absolutely dependent on plant specialized metabolites. How many times have you heard of resveratrol? That magical compound in red wine that gives you an excuse to drink just one more glass. We’ve all been told resveratrol improves heart health, and reduces chances of certain cancers. That perfume, or cologne you’re wearing? Its full of chemicals that were first identified in plants, and now synthesized by chemists. This assumes that the chemical mixture you’re wearing wasn’t directly isolated from plants and manufactured into the fragrance you just purchased. It’s quite possible you’re wearing a plant extract right now. Talk about au naturel! Ever had to take morphine, or codeine to kill intense pain after an accident or medical procedure? You guessed it, both of those molecules are from from plants, and specifically opium poppy (pictured above).
The availability of these valuable molecules isn’t as limitless as you may think. Taking morphine as a specific example; Western society, which makes up only 20% of the world’s population, consumes more than 95% of the annual medicinal morphine supply (ICOS, 2005). This is a small molecule that has amazing abilities to improve the quality of life for people undergoing palliative, end of life care. It should not be monopolized by a small fraction of society.
Because these plant derived specialized metabolites are so important to our every day lives there has been intense research to understand how they are are made in plants.
How are specialized metabolites formed?
Plant specialized metabolites are made from so-called primary metabolites. Examples of primary metabolites are the five carbon isoprene units that are involved in generating terpenes (eg. taxol), or amino acids that are involved in generating alkaloids (eg. morphine) and phenylpropanoids (eg. resveratrol).
The specifics of the of how these molecules are built isn’t important for this blog post. I just feel it’s necessary to demonstrate that these molecules aren’t made out of nothingness. They are made from resources that basically every single organism on the planet can synthesize themselves, or has access to.
Chemical diversity in plants
There are an estimated 250,000 different plant species on the planet and estimates peg the number of specialized metabolites at possibly above 100,000 (Verpoorte, R, 1998). Much like the early estimates of human genome protein coding gene numbers were off by orders of magnitude (2,000,000 in 1960, vs. 20,687 in 2012), I would predict that there are many more small molecules then 100,000.
Theories explaining chemical diversity in plants
For the better part of the 20th century natural product chemists, and microbiologists have put forward the notion that specialized metabolites are the product of aberrant metabolism. That they are accidental by-products of primary, essential metabolisms. Their sole purpose is to be strange forms of resource storage. This assumes the natural product chemists concede that these molecules have any intended functions at all. In fact, if biologists were to document any biological activity derived from these small molecules, like I noted before for resveratrol, and for morphine, then these functions are happenstance (Jones, D, 1972).
On the other side of the argument are the chemical ecologists, who since the latter part of the 20th century have argued that all specialized metabolites have function. Why else would plants invest significant resources in their synthesis? If these small molecules had no function, as aberrant metabolism protagonists would suggest, plants would be expected to re-purpose these resources towards core, beneficial activities like growth/replacement of foliage, and the only biological imperative, reproduction. And if chemical ecologists were to concede that any one small molecule in-fact had no biological function, then its existence can be explained in that it had function in the past. As it exists now, it has been modified ever so slightly, relative to its ancestral functional form, or whatever biological target it worked on in the environment has ceased to exist. There simply hasn’t been enough time, evolutionarily speaking, to shut down its synthesis. (Despres, L., et al. 2007; Dawkins, R., Krebs, J., 1979)
Biological (biomolecular) activity is an inherently rare trait for any one molecule to possess
What the chemical ecologists seem to ignore is that large scale plant screening programs intended to identify discrete biological activities (eg. NCI anti-cancer, insect deterring) have come up nearly empty handed. All large scale plant screening programs seem to identify activities of interest in less than 5% of screened plants (Jones, Firn, 2003).
This is an incredible discovery! Plant specialized pathways can have many dozens of steps towards any specific molecule. Supplying resources in the form of substrates, co-substrates, cofactors, synthesizing enzymes, replacing enzymes during enzyme turnover, regulating the biochemical pathways properly, maintaining scaffolds that enzymes are built on, even generating whole biochemically specialized cell types (eg. trichomes), involves MASSIVE resource investments. It boggles the mind that plants invest in these activities if success rates are so low in the small molecule products they generate. Why not invest in other more central functions like reproduction, and growth?
Because plants have no other choice
As mentioned before, plants can’t interact in their environments in the same ways that animals, insects and bacteria do. Plants instead depend on chemical effectors. Put another way; plants have no choice but to make do, accept the economic disadvantage specialized metabolism has, and work as best as they can with the cards they have been dealt. One of the cards they had available to them was chemistry. In the same way that Oscar Leonard Carl Pistorius (‘blade runner‘) was born with what many would consider a raw deal, but has worked with the resources available to him and has become a premier world-class sprinter, plants have also become arguably the most successful kingdom of organisms on the planet.
Reconciliation: The Screening Hypothesis
While proponents of the chemical arms race seem to ignore the low biological hit rates of large scale screening programs, Firn and Jones, who first proposed the screening hypothesis back in 1991, made it the raison-d’etre (Firn, Jones, 1991). They proposed that for plants to be fit they necessarily had to adapt strategies to synthesize and screen many molecules for biological functions. If biological activity is indeed such a rare trait, then how else would any given plant hope to find the single rare anti-herbivore, anti-pathogen, or pollinator attracting molecules?
It was also expected that plants would adopt strategies to reduce resource costs in performing such tasks. Ways to reduce costs from the perspective of biochemical costs would be to employ enzymes that have high substrate specificities (eg. gibberellin P450s), or enzymes that can make many products (eg. terpene synthases). In either case you have single enzymes working on, or generating multiple small molecules. You can think of these enzymes as the Swiss Army Knives of plants.
There are of course ways that biochemical pathways can be organized to reduce costs as well. Sufficed to say these organization structures are everywhere in every organism (eg. branched, converging or matrixed biochemical pathways in plants).
And while the low biological activity hit rates would seem to support the notion of aberrant metabolism, the phenomenal complexity, and length of biochemical pathways, their remarkably tight regulation (developmentally and in response to stimuli), and compartmentalization of these biochemical events seems to argue otherwise. I simply can not imagine a single argument that supports the immense resources plants dedicate towards specialized metabolism that is rooted in biology/evolution and argues in favor of aberrant metabolism.
Where do we go now?
I think it’s important to to emphasize that everything presented here are early stage theories. That while evolution is as close to a fact as anything in biology can get, irrespective of what Creationists would have you believe, the principles that I’ve reviewed here aren’t as well supported as the principle of evolution in general.
These evolutionary platforms of aberrant metabolism, the chemical arms race, and the screening hypothesis, are used to explain the chemical diversity in plants and they need further investigation. Nevertheless, I think it’s a great step forward for plant biochemists to consider ideas that incorporate evidence that most small molecules have no real biological function in planta. Alternatively, it’s time for us to get out there to devise unique, and creative strategies to further test the biological activity hit rates of plant small molecules.
Jones, DAVID A. “Cyanogenic glycosides and their function.” Phytochemical ecology 103 (1972): 124.
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