From Geo-Logic to Bio-Logic

Why did ATP become the central energy currency and all-around utility molecule, at the origin of life?

The exploration of the solar system and astronomical objects beyond has been one of the greatest achievements of humanity, and of the US in particular. We should be proud of expanding humanity's knowledge using robotic spacecraft and space-based telescopes that have visited every planet and seen incredibly far out in space, and back in time. But one thing we have not found is life. The Earth is unique, and it is unlikely that we will ever find life elsewhere within traveling distance. While life may concievably have landed on Earth from elsewhere, it is more probable that it originated here. Early Earth had as conducive conditions as anywhere we know of, to create the life that we see all around us: carbon-based, water-based, precious, organic life.

Figuring out how that happened has been a side-show in the course of molecular biology, whose funding is mostly premised on medical rationales, and of chemistry, whose funding is mostly industrial. But our research enterprise thankfully has a little room for basic research and fundamental questions, of which this is one of the most frustrating and esoteric, if philosphically meaningful. The field has coalesced in recent decades around the idea that oceanic hydrothermal vents provided some of the likeliest conditions for the origin of life, due to the various freebies they offer.

Early earth, as today, had very active geology that generated a stream of reduced hydrogen and other compounds coming out of hydrothermal vents, among other places. There was no free oxygen, and conditions were generally reducing. Oxygen was bound up in rocks, water, and CO2. The geology is so reducing that water itself was and still is routinely reduced on its trip through the mantle by processes such as serpentinization.

The essential problem is how to jump the enormous gap from the logic of geology and chemistry, over to the logic of biology. It is not a question of raw energy- the earth has plenty of energetic processes, from vocanoes and tectonics to incoming solar energy. The question is how a natural process that has resolutely chemical logic, running down the usual chemical and physical gradients from lower to higher entropy, could have generated the kind of replicating and coding molecular system where biological logic starts. A paper from 2007 gives a broad and scrupulous overview of the field, featuring detailed arguments supporting the RNA world as the probable destination (from chemical origins) where biological logic really began. 

To rehearse very briefly, RNA has, and still retains in life today, both coding capacity and catalytic capacity, unifying in one molecule the most essential elements of life. So RNA is thought to have been the first molecule with truly biological ... logic, being replaced later with DNA for some of its more sedentary roles. But there is no way to get to even very short RNA molecules without some kind of metabolic support. There has to be an organic soup of energy and small organic molecules- some kind of pre-biological metabolism- to give this RNA something to do and chemical substituents to replicate itself out of. And that is the role of the hydrothermal vent system, which seems like a supportive environment. For the trick in biology is that not everything is coded explicitly. Brains are not planned out in the DNA down to their crenelations, and membranes are not given size and weight blueprints. Biology relies heavily on natural chemistry and other unbiological physical processes to channel its development and ongoing activity. The coding for all this, which seems so vast with our 3 Gb genome, is actually rather sparse, specifying some processes in exquisite detail, (large proteins, after billions of years of jury-rigging, agglomeration, and optimization), while leaving a tremendous amount still implicit in the natural physical course of events.

A rough sketch of the chemical forces and gradients at a vent. CO2 is reduced into various simple organic compounds at the rock interfaces, through the power of the incoming hydrogen rich (electron-rich) chemicals. Vents like this can persist for thousands of years.

So the origin of life does not have to build the plane from raw aluminum, as it were. It just has to explain how a piece of paper got crumpled in a peculiar way that allowed it to fly, after which evolution could take care of the rest of the optimization and elaboration. Less metaphorically, if a supportive chemical environment could spontaneously (in geo-chemical terms) produce an ongoing stream of reduced organic molecules like ATP and acyl groups and TCA cycle intermediates out of the ambient CO2, water, and other key elements common in rocks, then the leap to life is a lot less daunting. And hydrothermal vents do just that- they conduct a warm and consistent stream of chemically reduced (i.e. extra electrons) and chemical-rich fluid out of the sea floor, while gathering up the ambient CO2 (which was highly concentrated on the early Earth) and making it into a zoo of organic chemicals. They also host the iron and other minerals useful in catalytic conversions, which remain at the heart of key metabolic enzymes to this day. And they also contain bubble-like stuctures that could have confined and segregated all this activity in pre-cellular forms. In this way, they are thought to be the most probable locations where many of the ingredients of life were being generated for free, making the step over to biological logic much less daunting than was once thought.

The rTCA cycle, portrayed in the reverse from our oxidative version, as a cycle of compounds that spontaneously generate out of simple ingredients, due to their step-wise reduction and energy content values. The fact that the output (top) can be easily cleaved into the inputs provides a "metabolic" cycle that could exist in a reducing geological setting, without life or complicated enzymes.

The TCA cycle, for instance, is absolutely at the core of metabolism, a flow of small molecules that disassemble (or assemble, if run in reverse) small carbon compounds in stepwise fashion, eventually arriving back at the starting constituents, with only outputs (inputs) of hydrogen reduction power, CO2, and ATP. In our cells, we use it to oxidize (metabolize) organic compounds to extract energy. Its various stations also supply the inputs to innumerable other biosynthetic processes. But other organisms, admittedly rare in today's world, use it in the forward direction to create organic compounds from CO2, where it is called reductive or reverse (rTCA). An article from 2004 discusses how this latter cycle and set of compounds very likely predates any biological coding capacity, and represents an intrisically natural flow of carbon reduction that would have been seen in a pre-biotic hydrothermal vent setting. 

What sparked my immediate interest in all this was a recent paper that described experiments focused on showing why ATP, of all the other bases and related chemicals, became such a central part of life's metabolism, including as a modern accessory to the TCA cycle. ATP is the major energy currency in cells, giving the extra push to thousands of enzymes, and forming the cores of additional central metabolic cofactors like NAD (nicotine adenine dinucleotide), and acetyl-CoA (the A is for adenine), and participating as one of the bases of DNA and RNA in our genetic core processes. 

Of all nucleoside diphosphates, ADP is most easily converted to ATP in the very simple conditions of added acyl phosphate and Fe3+ in water, at ambient temperatures or warmer. Note that the trace for ITP shows the same absorbance before and after the reaction. The others show no reaction either. Panel F shows a time course of the ADP reaction, in hours. The X axis refers to time of chromatography of the sample, not of the reaction.

Why ATP, and not the other bases, or other chemicals? Well, bases appear as early products out of pre-biotic reaction mixtures, so while somewhat complicated, they are a natural part of the milieu. The current work compares how phosphorylation of all the possible di-phosphate bases works, (that is, adenosine, cytidine, guanosine, inosine, and uridine diphosphates), using the plausible prebiotic ingredients ferric ion (Fe3+) and acetyl phosphate. They found surprisingly that only ADP can be productively converted to ATP in this setting, and it was pretty insensitive to pH, other ions, etc. This was apparently due to the special Fe3+ coordinating capability that ADP has due to its pentose N and neighboring amino group that allows an easy electron transfers to the incoming phosphate group. Iron remains common as an enzymatic cofactor today, and it is obviously highly plausible in this free form as a critical catalyst in a pre-biotic setting. Likewise, acetyl phosphate could hardly be simpler, occurs naturally under prebiotic conditions, and remains an important element of bacterial metabolism (and transiently one of eukaryotic metabolism) today. 

Ferric iron and ATP make a unique mechanistic pairing that enables easy phosphorylation at the third position, making ATP out of ADP and acyl phosphate. At step b, the incoming acyl phosphate is coordinated by the amino group while the iron is coordinated by the pentose nitrogen and two existing phosphates.

The point of this paper was simply to reveal why ATP, of all the possible bases and related chemicals, gained its dominant position of core chemical and currency. It is rare in origin-of-life research to gain a definitive insight like this, amid the masses of speculation and modeling, however plausible. So this is a significant step ahead for the field, while it continues to refine its ideas of how this amazing transition took place. Whether it can demonstrate the spontaneous rTCA cycle in a reasonable experimental setting is perhaps the next significant question.

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