The Origins of Life ~ Spontaneous synthesis?

RNA is suspected to have been an early lifelike molecule on Earth in part because of its supreme importance to modern life. RNA polymers carry DNA’s genomic messages out of the nucleus and into the body of the cell, where they are used to assemble strings of amino acids. The ribosome, the critical piece of cellular machinery that translates those RNA messages into life-sustaining proteins, is, at its core, itself composed of RNA. And ATP, the universal energy currency in the cell, is a slightly modified RNA monomer.

But a long-standing weakness of the RNA-world hypothesis has been the inability to spontaneously generate the molecule’s component nucleotides from the basic ingredients presumed to be available on the prebiotic Earth. Still today, “nobody has made all four of the nucleotides from one pot of simple starting materials,” says Georgia Tech biochemist Nicholas Hud.

In particular, ribose, the five-carbon sugar that constitutes RNA’s backbone, is difficult to form under prebiotic conditions, and purine and pyrimidine nucleobases, the variable parts of nucleotides, do not efficiently form covalent bonds with ribose. (See illustration.) Myriad simulations in the lab, however, have yielded some promising answers. In 2009, for example, John Sutherland of the MRC Laboratory of Molecular Biology in the U.K. and colleagues demonstrated the formation of the pyrimidine nucleotides, cytidine (C) and uridine (U), from a handful of plausible prebiotic molecules under conditions consistent with current early-Earth geochemical models.

Rather than rely on free ribose and nucleobases, the team sequentially derived the complete ribonucleotides from glycolaldehyde and glyceraldehyde—“the smallest molecules you might consider sugars,” explains Powner, a collaborator on the study. And in September 2012, Sutherland showed that these sugar building blocks could be derived from hydrogen cyanide, a suspected prebiotic molecule important in synthesizing amino acids.

Scientists have yet to produce the purine nucleotides adenosine (A) and guanosine (G) under similar prebiotic conditions, but the research is moving in that direction, says Powner. “There’s nothing I see, other than time and effort and a few bright ideas, that stands in the way of understanding at least [the] chemistry to the monomeric components of biology,” he says.

Powner and others are now turning to a different challenge: how those nucleotides link up into a molecule even a fraction as complex as modern RNAs. “How [do] you control polymer synthesis, polymer length, the interaction of macromolecular structures? And how [do] you make things that will specifically function as polymers, without getting a statistical mess?” Powner asks. “That’s where I see the synthetic area of this chemistry at the moment.”

One challenge of RNA polymerization is that there isn’t just one way for two nucleotides to bind. The phosphate group can link the 5’ carbon molecule of one sugar with either the 2’ carbon or the 3’ carbon of its neighbor. In life, thanks to the oversight of RNA polymerase, all RNAs are assembled by 3’–5’ phosphodiester linkages. But when generating RNAs in vitro, researchers get a mixture.

Last April, Powner, Sutherland, and their colleagues published evidence that a chemoselective acetylation process could support the generation of 17-nucleotide-long RNA molecules with predominantly 3’–5’ linkages under prebiotic conditions.4 In the same issue of Nature Chemistry, Powner and other colleagues also showed that the presence of a mixture of different RNA linkages within a polymer didn’t matter: it did not disrupt the folding of the molecules, nor their catalytic functions.

Meanwhile, Lehman’s group is unearthing evidence that if some small RNA polymers did arise, they may have had a fighting chance. Short oligomers of RNA, approximately 50 to 100 nucleotides long, are capable of recombining, bringing together different RNA units.6 “So as long as there’s an abiotic mechanism for producing small pieces of RNA, if you can recombine those pieces together, you can start building up your repertoire of catalysts,” Lehman says. And last year, he found that RNA fragments can be recycled,7 which could have helped generate the ample supply of nucleotides needed to support the replication and exponential growth of genetic elements.

To Lehman, the chemical pieces of the puzzle are falling into place. “I’m optimistic that within 5 or 10 years, we will indeed have a chemical route from the stuff that was laying around on the prebiotic earth to RNA or something quite close to RNA.”

References

D. Ritson, J.D. Sutherland, “Prebiotic synthesis of simple sugars by photoredox systems chemistry,” Nat Chem, 4:895-99, 2012.

F.R. Bowler et al., “Prebiotically plausible oligoribonucleotide ligation facilitated by chemoselective acetylation,” Nat Chem, 5:383-89, 2013.

A.E. Engelhart et al., “Functional RNAs exhibit tolerance for non-heritable 2’–5’ versus 3’–5’ backbone heterogeneity,” Nat Chem, 5:390-94, 2013.

#pathway #protein #RNAworld