Metabolism First and the Origin of Life

There are several competing hypotheses about the origin of life. Most people know about the Primordial Soup scenario; that's the one where complex organic molecules are created by spontaneous chemical reactions. Over time these complex molecules, such as amino acids and nucleotides, accumulate in a warm little pond and eventually they come together to form proteins and nucleic acids.

The RNA World scenario is similar except that nucleic acids (RNA) are thought to form before proteins. For a while, RNA molecules are the main catalysts in the primordial soup. Later on, proteins take over some of the catalytic roles. One of the problems with the RNA world hypothesis is that you have to have a reasonable concentration of nucleotides before the process can begin.

The third hypothesis is called Metabolism First. In this scheme, the first reactions involve spontaneous formation of simple molecules such as acetate, a two-carbon compound formed from carbon dioxide and water. Pathways leading to the synthesis of simple organic molecules might be promoted by natural catalysts such as minerals and porous surfaces in rocks. The point is that the origin of life is triggered by the accumulation of very simple organic molecules in thermodynamically favorable circumstances.

Simple organic molecules can then be combined in various ways that result in simple amino acids, lipids, etc. These, in turn, could act as catalysts for the formation of more organic molecules. This is the beginning of metabolism.

Eventually simple peptides will be formed and this could lead to better catalysts. Nucleic acids and complex amino acids will only form near the end of this process.

One of the advantages of the metabolism first scenario is that it offers a simple "solution" to the chirality/racemization problem by explaining why all naturally occurring amino acids are left-handed [see Can watery asteroids explain why life is 'left-handed'?]. Another advantage is that it doesn't require spontaneous formation of nucleotides—a major limitation of the RNA world scenario since spontaneous formation of such molecules is very improbable.¹

James Trefil, Harold Morowitz, and Eric Smith have written up a very nice summary of the Metabolism First hypothesis for American Scientist: The Origin of Life. The subtitle, "A case is made for the descent of electrons," is a clever play on words. It illustrates the point that synthesis of simple organic molecules such as acetate are thermodynamically favorable. This is science writing at its best.²

The authors have reconstructed the simplest, most fundamental, biochemical pathways concluding that a reductive citric acid cycle is probably the best example of the first metabolic pathway. In this pathway, the two-carbon acetate molecule is made from carbon dioxide and water in the reverse of the common citric acid pathway found in eukaryotes.

In fact, the reductive pathway occurs in many bacteria. They can still use it to fix carbon. The authors use the figure on the left to illustrate the basic pathway.

Almost all of the common molecules of life are synthesized from acetate or the molecules of the citric acid cycle. The simple amino acids, for example, are formed in one step. More complex amino acids are derived from the simple amino acids, etc. Similarly, simple fatty acids can be formed from acetate and more complex ones come later; once the simple ones accumulate.

The central role of citric acid cycle metabolism in biochemistry has been known for decades. It's involvement in biosynthesis pathways is often ignored in introductory biochemistry courses because they are heavily focused on fuel metabolism in mammals and biosynthetic pathways get short shrift in such courses.



The essence of Metabolism First is that the various complex molecules of life came after the spontaneous formation of very simple molecules. Pathways leading to the complex molecules evolved and their evolution was assisted by the evolution of various catalysts, some of which were biological in nature.

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1. In spite of the claims surrounding a recent paper in Nature: RNA world easier to make.

2. Probably good science editing as well. My friend Morgan Ryan is managing editor and he is very good.

[Photo Credit: American Scientist, courtesy of Scripps Institution of Oceanography, University of California, San Diego.]