The how, what, and why of HAP

Organic Chemistry and Enzyme Chemistry

Organic chemistry is about as equally organized as the art of making soup. You have a solvent, you throw your reactants into the solvent, you warm it up, you increase the pressure or reduce the pressure (some reactions are done at extreme low temperature conditions). The chemist creates the conditions that make the reactants in the solvents change their chemistry in the presence of one another, under those conditions. Usually for the reaction to be effected and then to last under normal world conditions, the conditions in the reactor differ greatly from prevailing external conditions, which means that the temperature will be either much higher or much lower than room temperature, the pH will be either much higher or much lower than normal pH, humidity, pressure differences and the solvent environment. And that will ensure that the reaction will not reverse itself or other reactions will not continue to occur once we have removed the resulting compound from the reactor. That’s how humans do chemistry and it’s called organic chemistry.

Plants employ enzymes to catalyze their chemical reactions. Enzymes will selectively effect a chemical reaction one molecule at a time. An enzyme is a type of functional protein. It is a name given to a piece of biological machinery (always a protein) that is always a specifically evolved catalyst for catalyzing a certain reaction.

The chemistry of bringing an amino acid into the world does occur naturally under conditions of what we call “the primeval soup”. In the conditions that prevail in the waters of the oceans of the earth (a lot of heat and sulphur and minerals coming out of the seabed together with flashes of lightning). In this environment chemical reactions were occurring and they brought forth amino acids spontaneously. Amino acids are not enzymes. Enzymes are proteins and proteins are made of hundreds or even thousands of amino acids in a very specific sequence (a different sequence for each protein).
Organic chemistry proceeds by throwing things into the mix and hoping something happens and when something does happen it is recorded in the annals of chemical abstracts, which is basically an archive of over more than 100 years of chemists reporting on how they have effected a synthesis. They write: “I did this I did that, these reactants under these conditions in the environment of that solvent yielded this result…”. As soon as you have several reliable reports, all indicating the same thing, that becomes a reliable reaction, which turns into a building block of organic chemistry. The role of the solvents is to provide different environments in which things happen. All of these reactions are molecules jiggling about, and they have different geometries to the way they jiggle which in turn will change the outcome of the reaction. Enzymes on the other hand take a completely different approach. They are shaped by evolution to recognize their substrates, and attach to them in a cell. When a metabolic enzyme recognizes that it is holding its two necessary substrates it will change its shape known as “changing conformation” and thereby it will force a change to take place. The substrates are the molecules on which the enzyme acts. Really the question that we are asking is, if we want to understand how feasible HAP is, what we are really asking is how promiscuous are enzymes in certain varieties of different plants. “Promiscuous” in that sentence means, will an enzyme act on substrates that it has never seen before. For example, will an aminotransferase, when it sees a ketone group, which it replaces with an amino group, will act only on the phytoprecursor of tryptophan? Or will it also swap a ketone with an amino on say, benzopropanone, thereby biosynthesizing amphetamine? Does the enzyme look at the entire context of the molecule on which it is performing the replacement? Or does it focus only on the presence of the group being replaced (ketone in this example)? Promiscuous enzymes are enzymes that will act on substrates that they are not familiar with.

Why Should Promiscuous Enzymes Exist?

There are two evolutionary forces at work in this arena. One for promiscuity and one against. With respects to primary metabolism and the creation of primary metabolites, enzymes will tend to be specific i.e. non-promiscuous because if you change anything about the function of the enzyme primary metabolism breaks. And primary metabolism is defined as the metabolic repertoire absolutely necessary to the survival of the organism. However with respect to secondary metabolism, it actually works for the benefit of the plant to be promiscuous (this is said from an evolutionary point of view). And for secondary metabolism the promiscuity of the enzymes allows the plant, in the presence of a variety of precursors to biosynthesize a variety of different metabolites. Both of these forces for promiscuity and against promiscuity are evolutionary realities. Every plant on the planet growing in the wild, if it was to have a chance to make it in nature, has to maintain a tight ship with respects to it’s primary metabolites. That’s because the lipids have to be made for the cell membranes, the membrane bound proteins and channels must be biosynthesized, and they all have to be functional in a way that will guarantee the plants’ survival so they cannot change very much. The entire photosynthesis pathway has to be present and has to be reliable in order to turn CO2 and water and the sun’s energy into sugar. All of the sugar transport pathways must be present and must be reliable (except in parasitic plants). Because sugar must be able to get to the roots and water must be able to get to the leaves. Normally, roots cannot make sugar because they have no access to light because they are stuck underground where it is dark and leaves have no access to water because they are not in the ground. Also the signaling mechanism between the root system and the foliage system has to work to keep the two systems synchronized with each other. So for all of these systems, specificity is high because any change to them reduces the survivability of the plant. But again, this pertains to primary metabolism – the bricks and mortar of the plants living mechanisms.
You want to strictly preserve your methods when it comes down to laying bricks and mortar. You rarely want to change anything. But when it comes to decorating the house – that’s when it pays off to be creative, because changes to decoration are not 'mission critical'. They can make the difference between a more attractive house and a less attractive one but they are not mission critical and will not make or break the ability to survive (when going back to the organism which is the metaphor of this example). That’s why secondary metabolite enzymes have an advantage by being promiscuous (or

“creative” to use the language of our metaphor). Plants are normally not lucky enough to be in a static environment. The insects and the animals, if the not the environment itself around them – are constantly changing. So it is beneficial for a plant to say, biosynthesize the pheromones of the predators of its herbivore attackers. But those pheromones keep changing and the pests keep changing. So the plant wants to, basically, change its “bag of tricks” as often as it can. “Whatever works” survives better. But when you shut off the promiscuity of that biosynthetic activity, you basically shut off development. Which guarantees that the plant will be outsmarted or outcompeted by its would-be predators, two, three or perhaps eight generations down the line.

All that said, I don’t think it is worth our while to spend too much time convincing ourselves that this is going to work, or too much time pondering whether it will work or not. Human Assisted Mycosynthesis has already been demonstrated, and fungi are much less promiscous then plants. The main path to discovery here is a curiosity driven, inspiration driven process. It must be planned and tried and when it leads to discoveries that actually work – we have something. So, I think it makes sense to discuss Efraim Lewinsohn’s aromatic melons, it makes sense to talk about the metabolism of carbamazepine in Israeli toxicity from Israeli vegetable irrigation – because there is literature showing that this phenomenon occurs in plants that have been watered with an external unnatural molecule which has been added to their feed. Additionally, there’s a very small body of literature, which talks about something called silent metabolism, which is the capability of plants to do things that nobody (including them) knew they could.

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