Then and Now: Matthew Powner Studies the Chemical Intersections at the Origins of Life

Back in 2014, organic chemist Matthew Powner was three years into leading his first independent lab at University College London when The Scientist interviewed him about his research. At the time, his group explored questions in the prebiotic synthesis of purines, a key step that must have occurred to produce the first nucleic acids on Earth.

Now, 12 years later, in honor of The Scientist’s 40^th anniversary, we contacted Powner to find out if his research had remained the same or had evolved. The origins of life still excite him, but his focus in this area has widened from nucleotide synthesis.

Shortly after his initial interview with The Scientist, Powner and his group discovered that a chemical reaction that separated sugar molecules also provided a way to produce precursors to proteinogenic amino acids, the amino acids that give rise to biological proteins, shedding light on the chemistry that led to life’s proteins. This discovery sent his group down a path studying amino acid synthesis. Recently, Powner and his team circled back to working with RNAs but now in the context of exploring how chemical reactions link specific amino acids to these nucleotides.

“The key for us is to understand which chemistries unite those molecules to allow all of them to come together at the same time, through the same types of processes, so that each can fulfill its niche to build a cell,” Powner said.

A Prebiotic Reaction at the Center of Early Biological Molecules

In the middle of the 2010s, Powner’s group was exploring how a key precursor molecule in RNA synthesis, aminooxazoline, reliably arose in prebiotic conditions. Synthesizing this molecule required the organic molecule cyanamide to first react with the sugar glycoaldehyde, and then the product from this reaction had to react with another sugar, glyceraldehyde. However, the known prebiotic synthesis reactions lead to the co-production of glycoaldehyde and glyceraldehyde with no way to orchestrate a selective and sequential reaction.

To solve this problem, Powner and his group considered ways to physically separate these two sugars in a prebiotic-relevant chemical reaction. They studied 2-aminothiazole, an amine molecule that was expected to be present in the prebiotic environment, as a mediator for this separation. First, they showed that the molecule could be produced through several reactions, then, they used it to crystallize glycoaldehyde. This allowed the necessary, sequential reaction with this sugar followed by glyceraldehyde to produce aminooxazoline for ribonucleotide synthesis.¹

While this approach answered the team’s nucleotide synthesis question, the reaction with 2-aminothiazole introduced them to a new line of investigation in prebiotic chemistry: how biologically-relevant amino acids were made.

Producing proteinogenic amino acids requires an aldehyde to react with ammonium cyanide. But the prebiotic environment would have contained aldehydes alongside other organic molecules. Similar to the sugar situation, these organic molecules would need to be separated somehow to promote the selective chemistry to yield biological amino acids.

Powner’s group realized that the reaction between 2-aminothiazole and glycoaldehyde formed a serine precursor, making them wonder if 2-aminothiazole could also help separate aldehydes from other organic molecules. Indeed, they found that it crystallized the aldehydes out of a mixture of organic compounds. From here, the researchers turned these aldehyde crystals into an aminonitrile that served as the base for proteinogenic amino acids.

“That [discovery] was the inspiration to then think about the amino acids,” Powner said. Powner then realized that this aminonitrile, because of its triple bond, is packed with energy. He considered whether, instead of hydrolyzing this compound into an amino acid that then needs more energy to create peptide bonds, whether it would be possible to use the high-energy aminonitrile directly in peptide synthesis.

“We had this new pathway that just lay before us, and we’re like ‘We have to look at this,’” Powner recalled. “That's what then led to our work in not just thinking about peptides, but having a new strategy, a different way of thinking about how to build the peptide bond.”

Continue reading below...

Whitepaper

Match Vacuum Performance to Your Application

Explore seven considerations that can influence workflow efficiency and material integrity

Read More

After exploring prebiotic peptide synthesis though these energy-rich aminonitriles, Powner reflected on the group’s discovery of the role of 2-aminothiazole in reactions that seemed to bridge RNA and amino acid chemistry.² Thinking about this sulfur-containing compound, he considered the important role of thiols in water for catalysts in prebiotic chemistry. “In life, there's one thiol that's, again, universal in the same way genetics and proteinogenic peptides are universal, and that's a molecule called pantetheine,” Powner said.

Pantetheine is the functional subunit of coenzyme A, a critical molecule in metabolism. It boasts a unique structure that resembles a peptide but includes chemical features that proteinogenic amino acids don’t contain. These observations led Powner and his team back to their reaction that isolated proteinogenic amino acids. However, instead of immediately proceeding with the reaction to produce aminonitriles, they left the precursors alone in the buffered water. In time, the researchers found that a new product emerged that they discovered had the correct structure to become pantetheine.³

Based on these findings, Powner and his group concluded that the same chemistry that gave rise to proteinogenic amino acids could, with just a little more time, produce another product with a distinct structure and an integral role in biochemistry. “I wouldn't have guessed that we could realistically have done that. That feels like the kind of thing that you'd probably need evolution and enzymes and sort of evolved feedback to improve the differentiation. But just the fact that it was spontaneous and absolute was remarkable to me.”

A Future Look into the Origins of Life Research

Seeing how the same chemistry could drive reactions integral to creating biological molecules in two different compound classes made Powner rethink how he understood prebiotic chemistry. Instead of seeing the reactions as individual processes, he and his team started thinking about them as nodes to connect biological molecules. “We just realized there was so much more to gain by looking more holistically at life's molecules and looking for those interconnections and using those interconnections to drive our science forward.”

Powner and his team brought in the idea of looking at biology holistically by studying how to use metabolic energy, with the help of thiol-containing molecules, to activate amino acids and selectively add nucleotides to these compounds.⁴ This work, Powner said, was “opening the door to start to investigate the chemistry that allows RNA to begin to control the synthesis of peptide bonds.”

Looking back on his career and reflecting on where he was when he first spoke to The Scientist, Powner admitted he never could have predicted the direction that his research went. “But that's because that's how science works. Some of the serendipity of what you find tends to be the interesting angles. The expected results often are less interesting than the ones that crop up, and you're like, ‘Okay, now that gives me a new idea,’” he said.

Powner added that, in the field of studying the origins of life, there are a plethora of unanswered or partially answered questions. “The challenge for people working in the field is not finding a question. There are so many questions, but picking the question you can make that bit of progress on, that you can unite something you're doing to something that's going to move you a step forward,” he said.