Is this the solution to a major origin-of-life mystery?

US researchers may have solved one of chemistry and biology’s biggest chicken-or-egg conundrums. Joel F. Hooper reports.

The origin of the citric cycle is a classic chicken-egg mystery – until now.
The origin of the citric cycle is a classic chicken-egg mystery – until now.
David Malan/Getty Images

Understanding the origin of life on earth is a daunting prospect. Piecing together events which took place around 3.8 billion years ago is extremely challenging, when scientists have to work backwards from complex and highly evolved modern life forms.

A new study by a group from the Scripps Research Institute in California may have provided a key piece to the puzzle, proposing a new chemical cycle which may have been at the core of early life.

All aerobic life-forms generate energy from stored sugars, fats or proteins via a chemical process called the citric acid (or TCA) cycle. This metabolic pathway takes two-carbon molecules (in the form of acetyl-CoA) and oxidises them to form two molecules of carbon dioxide. The energy released from this chemical process is harnessed to produce ATP, the energy source that is used to power cellular processes.

What puzzles scientists is that the citric acid cycle is highly complex, requiring at least 10 different enzymes to function. How could these enzymes have evolved, if a functioning citric acid cycle is fundamental to life? It’s the ultimate chicken-and-egg argument that has stumped scientists for years.

The eminent chemist and origin of life expert Leslie Orgel once said, “If complex cycles analogous to metabolic cycles could have operated on the primitive Earth before the appearance of enzymes or other informational polymers, many of the obstacles to the construction of a plausible scenario for the origin of life would disappear.”

Attempts to demonstrate a simplified citric acid cycle, which might have operated using the simple molecules available on prebiotic earth have been largely unsuccessful.

Now, the team at Scripps, led by Ramanarayanan Krishnamurthy, has identified a chemical pathway which performs a similar function to the citric acid cycle, but uses only simple molecules known to have been available on early earth.

The research is reported in the journal Nature Communications.

The team has linked together two chemical cycles, called the HKG cycle and the malonate cycle, which are able to take a simple two-carbon molecule (in the form of glyoxylate) and convert it into two molecules of CO2.

In the presence of ammonia, this process was also shown to produce aspartate, a simple amino acid which serves as a building block for proteins.

The authors propose that a metabolic process based on the HKG and malonate cycles may have served as an early template for what has now become the citric acid cycle. They also demonstrated that the chemical reactions proceed faster in the presence of iron sulfate, which fits with the theory that iron clusters served enzyme-like roles in early metabolism.

"The chemistry could have stayed the same over time, it was just the nature of the molecules that changed," says Krishnamurthy. "The molecules evolved to be more complicated over time based on what biology needed."

Joel Hooper is a senior research fellow at Monash University, in Melbourne, Australia.
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