Four billion years ago, the Earth looked much different than it does today, devoid of life and covered by a vast ocean. Over millions of years, life emerged in this primordial soup. Researchers have long theorized how the molecules came together to cause this transition. Now, scientists at Scripps Research have discovered a new set of chemical reactions that use cyanide, ammonia, and carbon dioxide—all thought to be common on the early Earth—to generate amino acids and nucleic acids, the building blocks of proteins and DNA.
“We invented a new paradigm to explain this shift from prebiotic to biotic chemistry,” said Ramanarayanan Krishnamurthy, PhD, associate professor of chemistry at Scripps Research and lead author of the new paper, published July 28, 2022 in the journal Natural chemistry. “We think the reactions we’ve described are probably what could have happened on the early Earth.”
In addition to giving researchers insight into the chemistry of the early Earth, the newly discovered chemical reactions are also useful in certain manufacturing processes, such as the generation of custom-labeled biomolecules from inexpensive starting materials.
Earlier this year, Krishnamurthy’s group showed how cyanide can activate chemical reactions that convert prebiotic molecules and water into essential organic compounds necessary for life. Unlike previously proposed reactions, this one works at room temperature and over a wide pH range. The researchers wondered if, under the same conditions, there was a way to generate amino acids, the more complex molecules that make up the proteins in all known living cells.
In today’s cells, amino acids are generated from precursors called α-keto acids, using both nitrogen and specialized proteins called enzymes. Researchers have found evidence that α-keto acids likely existed early in Earth’s history. However, many have hypothesized that before the appearance of cellular life, amino acids must have been generated from completely different precursors, aldehydes, rather than α-keto acids, since the enzymes to carry out the conversion did not yet exist. But this idea led to a debate about how and when the switch from aldehydes to α-keto acids as the key ingredient for amino acid production occurred.
After their success using cyanide to drive other chemical reactions, Krishnamurthy and his colleagues suspected that cyanide, even without enzymes, could also help convert α-keto acids to amino acids. Because they knew nitrogen would be needed in some form, they added ammonia, a form of nitrogen that would have been present on the early Earth. Then, through trial and error, they discovered a third key ingredient: carbon dioxide. With this mixture, they quickly began to see the formation of amino acids.
“We expected this to be quite difficult to figure out, and it turned out to be even simpler than we imagined,” says Krishnamurthy. “If you just mix the keto acid, the cyanide, and the ammonia, it just sits there. As soon as you add carbon dioxide, even trace amounts, the reaction speeds up.”
Because the new reaction is relatively similar to what happens in cells today — except that it’s driven by cyanide instead of protein — it seems more likely to be the source of early life than drastically different reactions, the researchers said. The research also helps bring together both sides of a long-standing debate about the importance of carbon dioxide to early life, concluding that carbon dioxide was key, but only in combination with other molecules.
In the process of studying their chemical soup, Krishnamurthy’s group discovered that a byproduct of the same reaction was orotate, a precursor to nucleotides that make up DNA and RNA. This suggests that the same primordial soup, under the right conditions, could have given rise to a large number of molecules that are necessary for the key elements of life.
“What we want to do next is to continue to explore what kind of chemistry can emerge from this mixture,” says Krishnamurthy. “Can amino acids start making small proteins? Can one of those proteins go back and start acting as an enzyme to make more of those amino acids?”
This work was supported by funding from the NSF Center for Chemical Evolution (CHE-1504217), a NASA Exobiology grant (80NSSC18K1300), and a Simons Foundation grant (327124FY19).