Nearly all forms of life use a process called "the citric acid cycle" to derive energy from carbohydrates, fats and proteins. Scientists have discovered how this critical process may have arisen on early Earth to enable life. 

Origin-of-life chemists discover plausible ancestor of essential metabolic process used by most plants and animals

A new study clarifies how a ‘chemical engine of life’ might have arisen from simple organic compounds on early Earth.

October 12, 2020

LA JOLLA, CA—A team of chemists from Scripps Research, in collaboration with scientists at Furman University, has illuminated the origins of chemical reactions that most animals and plants depend upon to derive energy from carbohydrates, fats and proteins.  

The reaction cycle—commonly referred to as the citric acid cycle, the TCA cycle or the Krebs cycle—is, like DNA and the genetic code, one of the fundamental features of life on Earth. In addition to enabling oxygen-based energy production, it yields some of the crucial molecular building blocks that cells use to repair and replicate themselves.

The origin of this critical chemical engine of life, in reactions that must have been possible on Earth before life arose, has long been a mystery.

However, in their study, published in Nature Chemistry, the chemists found that with just two organic compounds that would have been present on “prebiotic” Earth, they could obtain a chain of reactions closely resembling a large part of the modern TCA cycle.

“This sequence of prebiotic reactions could have set the stage for increasingly sophisticated pathways operating under the control of early life forms,” says study co-senior author Ramanarayanan Krishnamurthy, PhD, an associate professor in the Department of Chemistry at Scripps Research.

Krishnamurthy and his lab collaborated on the study with Greg Springsteen, PhD, professor of chemistry at Furman University.

Determining the pre-life ancestor of the TCA cycle has been a challenge not just because of the largely unknowable state of the early Earth, but also because the TCA cycle depends on enzyme “catalysts” that greatly boost the speed of the reactions and tie different chains of reactions together in a self-sustaining cycle. Enzymes are proteins made in cells, whereas in the pre-biotic world, there were no cells and thus no enzymes to act as catalysts for reactions.

Other proposals for a plausible prebiotic ancestor of the TCA cycle have included charged iron atoms—which can also act as reaction catalysts—in the role now taken by enzymes. But Krishnamurthy and Springsteen argue that such iron atoms, in a pre-biotic context, would have been too reactive, ultimately destroying the very molecules the cycle was intended to produce.

The chemists showed that two relatively simple “ketoacid” organic compounds, glyoxylate and pyruvate, which already play a role in the TCA cycle and related metabolic cycles, can react in water at normal temperatures to yield a sequence of several other ketoacids closely resembling a portion of the modern TCA cycle. And, when oxidized by reactions with the simple chemical hydrogen peroxide, they yield a set of compounds that actually comprise part of the modern TCA cycle.

That part of the TCA cycle normally contributes to the production of amino acids, the building blocks of proteins, which are the workhorse molecules of all cells.

Krishnamurthy and Springsteen demonstrated that under plausible conditions and in the presence of the simplest amino acid, glycine—which is generally believed to have existed on Earth before life arose—two of the ketoacids produced by their glyoxylate-pyruvate reactions can be converted into different amino acids.

The findings, therefore, at least hint at how a key part of the TCA cycle could have been available to early, rudimentary life forms even without enzymes or other catalysts.

“The observation that a pathway with striking similarities to modern biology can progress in water using simple starting materials provides support to the idea that something like this could have been active at or near the origin of life,” Springsteen says.

The researchers are continuing to investigate their new set of reactions as well as reactions that could explain the origins of other parts of the TCA cycle.

Besides Krishnamurthy and Springsteen, co-authors of the study, “A Plausible Metal-Free Ancestral Analogue of the Krebs Cycle Composed Entirely of α-Ketoacids,” were Trent Stubbs of Furman University and Mahipal Yadav, PhD, of Scripps Research. 

The research was supported by the Center for Chemical Evolution [CHE-1504217], a National Science Foundation–NASA program, and by NASA [80NSSC18K1300].

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