New advance in modeling the chemistry of the origin of life

Study demonstrates a closely related set of chemical reactions that could have supported the development of early life forms.

LA JOLLA, CA—One of the greatest, most enduring scientific mysteries concerns the origin of life on Earth. How could this complex system of self-replicating molecules, each component of which is heavily dependent on the others, have developed from the chemistry available on our then-lifeless planet roughly four billion years ago? Origin of Life chemists at Scripps Research have now made a significant advance in answering this fundamental question.

In a study reported in the chemistry journal Angewandte Chemie, the scientists demonstrated a set of related reactions that could have enabled the transition, on the primordial Earth, from pre-life chemistry to the biochemistry of the first simple life forms. The reactions yield molecular building blocks that can be stitched into DNA-like strands, either with the help of reaction-speeding organic catalyst molecules that were plausibly present before life arose, or with more efficient enzyme catalysts that early life forms would have used.

“This study is a proof of principle that the transition from an ‘abiotic’ world without enzymes to an early biological world that has enzymes could have involved the same chemistry throughout,” says study senior author Ramanarayanan Krishnamurthy, PhD, associate professor of chemistry at Scripps Research.

Every modern DNA-based organism makes its DNA from building blocks called nucleotides using highly evolved, highly efficient polymerase enzymes. These enzymes are themselves encoded in the organism’s DNA; they are, in other words, part of the world of biology, and were not present on the Earth before life arose. One of the big challenges, then, for origin of life researchers, is to explain how DNA, or its molecular cousin RNA, could have emerged from a world without enzymes.

In recent studies, Krishnamurthy and his colleagues have shown how an organic compound called diamidophosphate (DAP), with the help of another compound called imidazole—which acts as a non-enzyme catalyst—could have modified simple molecules called nucleosides into nucleotide building blocks closely resembling those of modern RNA and DNA. DAP, the imidazole and the nucleosides were all plausibly present on the early Earth before life arose. The researchers also have shown that such reactions could even have knitted the nucleotides into short, mini-DNA-like chains called oligonucleotides, which conceivably could have been the first self-replicators.

In the new study, the researchers showed that a similar DAP-mediated reaction, now using a chemical cousin of imidazole called aminoimidazole as a catalyst, can transform nucleosides into primitive nucleotides and oligonucleotides, but at the same time can also make nucleotide building blocks that are much more like those in contemporary biology, and are capable of being stitched into long strands by enzymes.

The work suggests that the same basic soup of chemical reactants could have yielded short oligonucleotides in a pre-enzyme world, and much longer, more DNA-like oligonucleotides in a living world that had begun to make enzymes.

That life-promoting chemistry could thus have driven the possibly eons-long transition from a lifeless, enzyme-less Earth to an Earth with a primitive biology including the first enzymes, Krishnamurthy says.

A key event that is presumed to have happened in this transition, he adds, is the appearance in the early, enzyme-free reactions of a short, primitive oligonucleotide that—either on its own or through its encoding of a primitive protein—had the enzyme-like ability to catalyze its own production.

“Then you would have a system in which the catalyst is able to use nucleosides in the environment to make more copies of itself—and with that onset of simple self-replication, the ingredients of biology would start to fall into place,” Krishnamurthy says.

Krishnamurthy and his colleagues now are working with the new reactions to see if they can produce such a self-catalyzing molecule, which would represent one of the last missing pieces of the Origin of Life puzzle.

Apart from its basic science significance, the research may bear fruit commercially, since it involves new and potentially more efficient and robust ways of synthesizing DNA and RNA—techniques that could have widespread applications in the worlds of biology and biotechnology.

Concurrent Prebiotic Formation of Nucleoside-Amidophosphates and Nucleoside-Triphosphates Potentiates Transition from Abiotic to Biotic Polymerization,” was co-authored by Huacan Lin, Eddy Jiménez, and Ramanarayanan Krishnamurthy of Scripps Research; and by Joshua Arriola and Ulrich Müller of the University of California San Diego.

The research was supported by a joint National Science Foundation and NASA program (CHE-150421), the Simons Foundation (327124FY19), and a grant from NASA (80NSSC19K0467).

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