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The origin of life on Earth has long eluded scientists. A key question is how much of the history of life on Earth has been lost to time. It is quite common for a species to “go extinct” using a biochemical reaction, and if this happens to enough species, such reactions can effectively be “forgotten” by life on Earth.

But if the history of biochemistry is full of forgotten reactions, will there be any way to tell? This question inspired researchers from the Earth Life Science Institute (ELSI) at the Tokyo Institute of Technology and the California Institute of Technology (CalTech) in the US. They reasoned that the forgotten chemistry would appear as interruptions or “breaks” in the path that chemistry takes from simple geochemical molecules to complex biological molecules.

The early Earth was rich in simple compounds like hydrogen sulfide, ammonia, and carbon dioxide—molecules not normally associated with sustaining life. But billions of years ago, early life relied on these simple molecules as a source of raw materials. As life evolved, biochemical processes gradually transformed these precursors into compounds that are still found today. These processes represent the earliest metabolic pathways.

To model the history of biochemistry, the ELSI researchers—Specially Appointed Associate Professor Harrison B. Smith, Specially Appointed Associate Professor Liam M. Longo, and Associate Professor Sean Erin McGlynn, in collaboration with CalTech researcher Joshua Goldford—needed an inventory of all known biochemical reactions , to understand what types of chemistry life can perform.

They turned to the Kyoto Encyclopedia of Genes and Genomes database, which catalogs more than 12,000 biochemical reactions. With reactions in hand, they began to model the stepwise development of metabolism.

Previous attempts to model the evolution of metabolism in this way have consistently failed to produce the most common, complex molecules used by modern life. However, the reason was not entirely clear. As before, when the researchers ran their model, they found that only a few compounds could be produced. The study was published in the journal Natural ecology and evolution.

One way around this problem is to push stagnant chemistry by manually providing modern compounds. The researchers took a different approach: they wanted to determine how many reactions were missing. And their hunt led them back to one of the most important molecules in all of biochemistry: adenosine triphosphate (ATP).

ATP is the cell’s energy currency because it can be used to drive reactions — like building proteins — that wouldn’t otherwise happen in water. However, ATP has a unique property: the very reactions that form ATP require ATP. In other words, unless ATP is no longer present, there is no other way for life today to produce ATP. This cyclical dependence was the reason why the model stalled.

How could this “ATP predicament” be solved? As it turns out, the reactive part of ATP is remarkably similar to the inorganic compound polyphosphate. By allowing ATP-generating reactions to use polyphosphate instead of ATP—by modifying a total of eight reactions—almost all of modern basal metabolism can be achieved. Researchers could then estimate the relative ages of all common metabolites and ask pointed questions about the history of metabolic pathways.

One such question is whether biological pathways were built in a linear fashion—in which one reaction after another is added sequentially—or whether the pathways’ reactions emerged as a mosaic, in which reactions from many different ages were brought together to form something new. The researchers were able to quantify this by finding that both types of pathways are almost equally common throughout metabolism.

But back to the question that inspired the study—how much biochemistry is lost over time? “We may never know exactly, but our study provided an important piece of evidence: only eight new reactions, all reminiscent of common biochemical reactions, are needed to link geochemistry and biochemistry,” says Smith.

“This does not prove that the space of missing biochemistry is small, but it does show that even reactions that have disappeared can be rediscovered from clues left in modern biochemistry,” Smith concludes.