Why ATP? Abiotic chemistry provides an answer

Nick Lane’s research group as UCL has found an answer to one of the most fundamental mysteries about the chemistry of life: Why do cells use ATP rather than any one of the other, equally capable nucleotide triphosphates? It turns out the answer is found uniquely in abiotic chemistry.

The ion Fe3+ will catalyze the phosphorylation of only ADP to ATP with acetyl-phosphate(AcP) under mild and anoxic conditions in water, whereas the reaction does not occur for any of the other nucleotides, and no other common ion or metabolic cofactor seems able to catalyze the reaction.

Thus prebiotic chemistry that would have almost certainly existed on the primordial Earth(high iron contents in water, no oxygen) answers this most fundamental question about the basic metabolic process of all known cellular life. This then, incidentally, also constitutes evidence that the metabolic processes of life on Earth began with prebiotic chemistry in an aqueous setting. And is thus evidence for a natural, physical and chemical origin of life, rather than any direct intelligent design, since in all extant life the phosphorylation of nucleotides is catalyzed by enzymes rather than abiotic chemistry.


ATP is casually referred to as the ‘universal energy currency’ of life. Why it gained this ascendency in metabolism, in place of many possible equivalents, is an abiding mystery in biology. There is nothing particularly special about the ‘high-energy’ phosphoanhydride bonds in ATP. Rather, its ability to drive phosphorylation or condensation reactions reflects the extraordinary disequilibrium between ATP and ADP – about 10 orders of magnitude in modern cells, pushed by free energy derived from respiration [1]. ATP drives intermediary metabolism through the coupling of exergonic to endergonic reactions via phosphorylation and hydrolysis, but other phosphorylating agents (including GTP and CTP) could be pushed equally far from equilibrium, and accomplish equivalent coupling. In fact, the centrality of ATP goes far beyond phosphorylation, as emphasised by the ubiquity of ATP derivatives in intermediary metabolism, including the ancient cofactors NADH, FADH and Coenzyme A (which all derive from ATP rather than AMP or adenine). ATP-coupled monomer activation also promotes the polymerisation of macromolecules, including RNA, DNA and proteins. Protein synthesis requires the activation of amino acids by adenylation (using ATP) before binding to tRNA, while the nucleotide triphosphates used for RNA and DNA synthesis are phosphorylated by ATP. So what, if anything, is special about ATP?

Notice how only ATP formation from ADP and AcP is catalyzed above the uncatalyzed rate by Fe3+:

Fig 4:

Phosphorylation of nucleotide diphosphates by AcP.

HPLC chromatogram of the resulting NTP of the phosphorylation of ( a ) adenosine diphosphate (ADP), ( b ) inosine diphosphate (IDP), ( c ) guanosine diphosphate (GDP), ( d ) cytidine diphosphate (CDP) and ( e ) uridine diphosphate (UDP) by AcP catalysed by Fe3+ at 30°C and pH ∼5.5–6 at the beginning of the reaction (0 h, broken line, blue) and after 3 hours (solid line, red). The molecular structure of each base forming the nucleotides is shown. ( f ) 31P–NMR spectrum of PPi (bottom, blue), PPPi (middle, red) and the reaction PPi (1 mM) + AcP (4 mM) + Fe3+ (500 μM) at 30°C and pH ∼5.5–6 after 3h (top, green).

The discovery that AcP can phosphorylate ADP to ATP in the presence of Fe3+ was serendipitous: while studying the electrolysis of ADP in the presence of AcP, Kitani et al . noted a ∼20 % conversion of ADP to ATP as the iron electrode they were using in their setup corroded [32]. But the fact that substrate-level phosphorylation of ADP to ATP can be accomplished by AcP in water says nothing about whether this mechanism actually holds prebiotic relevance. We have therefore explored the phosphorylation of ADP more systematically using a range of prebiotically plausible and biologically relevant phosphorylating agents, and a panel of metal ions as possible catalysts. We find that the combination of Fe3+ and AcP is unique: no other metal ions or phosphorylating agents are as effective at phosphorylating ADP. Equally striking, we find that ADP is also unique: the combination of AcP and Fe3+ will phosphorylate ADP but not GDP, CDP, UDP or IDP, nor free pyrophosphate. We use these data and the reaction kinetics to propose a possible mechanism. Our results suggest that ATP became established as the universal energy currency in a prebiotic, monomeric world, on the basis of its unusual chemistry in water.


Our results support the following conclusions: (i) acetyl phosphate (AcP) efficiently phosphorylates ADP to ATP, but only in the presence of Fe3+ ions as catalyst ( Fig. 1 ); (ii) the reaction takes place in water and can occur in a wide range of aqueous environments ( Fig. 2 ); (iii) no other phosphorylating agent tested was as effective as AcP ( Fig. 3 ); and (iv) adenine is unique among canonical nucleobases in facilitating the phosphorylation of its nucleotide diphosphate to the triphosphate ( Fig. 4) . Taken together, these findings suggest that the pre-eminence of ATP in biology has its roots in aqueous prebiotic chemistry. The substrate-level phosphorylation of ADP to ATP by AcP is uniquely facilitated in water under prebiotic conditions and remains the fulcrum between thioester and phosphate metabolism in bacteria and archaea today [2]. This implies that ATP became the universal energy currency of life not as the endpoint of genetic selection or some frozen accident, but for fundamental chemical reasons, and probably in a monomer world before the polymerization of RNA, DNA and proteins.

The work presented here provides a compelling basis for each of these statements, but also raises a number of questions. Why ferric iron? Unlike AcP or ATP itself there is no clear link with biology in this case; we had expected other ions more commonly associated with nucleotides, notably Mg2+ or Ca2+ [39,40], to play a more clear-cut role. In fact, their catalytic effect was only noticeable in the presence of Fe3+, as has been reported before, whereas higher concentrations, equivalent to modern ocean conditions, precluded ATP synthesis. We infer that the reason Fe3+ plays a unique role relates in part to its high charge density and small ionic radius. The fact that only ADP could be phosphorylated among canonical nucleobases suggests that Fe3+ interacts directly with the N6 amino group on the adenine ring as well as the N7 previously noted by others [6063]. But the interactions between Fe3+ and the N7 moiety alone cannot explain our results, as no triphosphate was formed in the absence of the N6-amino group, for example in the case of GDP. The fact that ADP is phosphorylated more readily than AMP ( SI Fig. 5 ) indicates that Fe3+ also interacts with the diphosphate tail of ADP. And the fact that the optimal stoichiometry of Fe3+ to ADP is 1:1, coupled with the absence of evidence for stacking of bases by MALDI-ToF ( Fig. 5 ), indicates that a single Fe3+ ion interacts with a single ADP, and necessarily also with a single AcP.



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Very. This is actually also another small hint that some aspects of biochemistry might be universal.

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While it is a different form of iron (Fe2+, not Fe3+) in the following report, I think it is thought-provoking to reflect on how iron may have been a (the?) primordial metal cation for a lot of important pre-biotic chemistry:


The story of fundamental biochemical reactions promoted by iron doesn’t stop there:


Wow! I’m late to the table—and just added a 14th “like” to this thread’s OP—but this is amazing. I suppose the mainstream media gave it little notice but even to a non-biologist like me, this seems like a really big deal.

This kind of thread is one of the main reasons I read Peaceful Science.

Even for a layperson, the Figures from the quoted article are incredibly hard-hitting.

Thanks for posting this news and explanation, @Rumraket.

(@Art’s link to the Higgs & Pudritz abstract was also quite amazing.)

I use threads like this one to invite people to PS.


The paper was only just posted on bioarxiv a few says ago, I doubt anyone has picked up on it yet. I definitely expect more press around it when it appears in a proper journal. It really is big news.

I know more big surprises are coming from Nick Lane’s group on a range of fundamental questions around the origin of life from a talk of his I saw recently, and this ATP stuff was one of the things mentioned. So I was on the lookout for this one and posted as soon as it turned up.

Some say there’s no progress in abiogenesis research. Go figure…


Is the argument that life couldn’t plausibly use anything but ATP?

No on the contrary. The argument is (also explained well in the paper) that any of the known ribonucleotide triphosphates could in principle perform the role ATP does in metabolism. GTP, CTP, UTP, TTP, and even the ATP precursor ITP could function as an energy currency.
The sodium or proton disequilibrium between the cytoplasm and periplasmic space could in principle be exploited to phosphorylate the other nucleotides to the triphosphate form given a machine similar to ATP synthetase, and we could (I suppose) call such a machine GTP synthetase, UTP synthetase, or whatever, instead of ATP synthetase. There is no physical barrier preventing this from being how life functions. A chemical disequilibrium between UDP and UTP could be exploited to do work just as well as the disequilibrium between ADP and ATP can.
Heck, there are even a few cellular processes that use GTP for example. But the phosphorylation of all of the nucleotides in life is today catalyzed by enzymes rather than Fe3+, and does not seem to just occur spontaneously. A catalyst is needed to couple NDP with phosphate to get NTP.

So the question we were left with is why, given so many options (enzymes could be making TTP, or CTP instead of ATP), we end up with life using almost exclusively ATP and ATP derivatives?

I think the argument is that given the absence of enzymes, and the absence elaborate molecular machines like ATP synthetase (they’re not prebiotically plausible) - and given a range of alternative plausible abiotic catalysts (metals or minerals) - only adenosine can be phosphorylated to it’s triphosphate form with an appreciable yield. So given that we now have evidence that only adenosine can be phosphorylated given the tested range of very plausible prebiotic conditions, this immediately provides us with an explanation for the centrality of this molecule in life as we know it. The phosphorylation chemistry of ADP to ATP with AcP occurs readily under the highly plausible prebiotic environment conditions tested, while it does not occur for the other nucleosides.


Not an argument, a hypothesis predicting that at least some of the features of life that appear to be arbitrary choices, like the obsession with moving protons across membranes and using ATP as the primary energy currency, predict that we will find reasons for their selection in abiotic chemistry.

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