The evolution of metabolic enzymes in LUCA, Bacteria, and Archaea

The best scenario for the origin of life is that it first arose in hydrothermal vents deep in the ocean. The first catalysts of metabolic reactions were metals and later on simple organic molecules bound to metals. The substrates for all reactions were inorganic compounds such as H₂, CO₂, NH₃, H₂S and phosphate/phosphite.

Over time, the inorganic catalysts were gradually replaced by protein and RNA catalysts that often incorporated the metal ions into their active sites or used cofactors containing metal ions. There are about 400 basic metabolic reactions that are fundamental to life. Some enzyme catalysts are very ancient but others seem to be more recent.

A large group of researchers set out to discover the enzymes that are common to all life and they concluded that only about half of these enzymes are common to all forms of life. They propose that LUCA (last universal common ancestor) still had quite a few metabolic reactions that were catalyzed by inorganic catalysts (metals).

Gradually two distinct forms of life evolved from LUCA: Bacteria, and Archaea. Each group evolved distinct protein enzymes for a number of reactions that were catalyzed by metals in LUCA. Examples include alanine dehydrogenase, shikimate kinase and dozens of others.

Mrnjavac, N., Hoffmann, N.K., Schlikker, M.L., Burmeister, M., Schwander, L., Garcia, C.G., Brabender, M., Steel, M., Huson, D.H., Metzger, S., Dherbassy, Q., Schink, B., Basen, M., Moran, J., Tuysuz, H., Preiner, M. and Martin, W.F. (2026) Intermediate stages in the origin of metabolism at a phosphorylating hydrothermal vent. Science Advances 12:eaef3128. [doi: 10.1126/sciadv.aef3128]

The origin of life required the emergence of metabolism, an autocatalytic network of enzymatic reactions that synthesize amino acids, nucleotides, and cofactors. At the origin of metabolism, there were no enzymes—how did it start? Empirical studies addressing early metabolic evolution are lacking. Harnessing protein structures for metabolic enzymes, we identify intermediate states in primordial metabolic assembly. We show that enzymatic metabolism in the universal common ancestor was incomplete, undergoing final assembly independently in the lineages leading to bacteria and archaea. Native transition metals—iron, cobalt, nickel, and palladium—served as the catalytic forerunners of both enzymes and cofactors at metabolic origin, while phosphite supplied energy, as it phosphorylates adenosine 5′-monophosphate to adenosine 5′-diphosphate and serine to phosphoserine using native metal catalysts in water. Phosphite and native metals occur in serpentinizing hydrothermal systems, identifying an energy-supplying, catalytic site of metabolic origin. Cofactors liberated nascent metabolism from native metal catalysts, engendering its autocatalytic state.

There's much more in this paper. It includes a detailed discussion of known metal-catalyzed reactions that account for 47% of the fundamental reactions of life. There's a lot of discussion about phosphorus and how it might have been incorporated into organic molecules. There's documented support for the existence of the acetyl-CoA pathway for the reduction of CO₂ to pyruvate—this is widely thought to be the primary pathway of carbon fixation in early cells. [Anaerobic carbon fixation in ancient prokaryotes]

The authors include an intriguing diagram of metabolism at a phosphorylating hydrothermal vent where black lines indicate metal-catalyzed reactions, gold lines indicate the evolution of replacement enzyme-catalyzed reactions in LUCA, and blue and red lines indicate subsequent replacements in bacteria (LBCA) and archaea (LACA) respectively.

Details that could throw doubt on your interpretation must be given, if you know them. You must do the best you can—if you know anything at all wrong, or possibly wrong—to explain it. If you make a theory, for example, and advertise it, or put it out, then you must also put down all the facts that disagree with it as well as those that agree with it.

Richard Feynman (1985)
"Cargo Cult Science"
in Surely You're Joking, Mr. Feynman"

While much of this is speculative, the existing evidence is discussed and reviewed in a lengthy and logical manner that includes raising and commenting on all the criticisms and difficulties inherent in this field. This is the way good papers should be written. (ENCODE scientists take note.)

When I read a paper that's outside of my area of expertise, I often have difficulty judging whether the authors are credible or not. This is a constant problem with the scientific literature.

It's very difficult to teach students that they should be skeptical and even more difficult to teach them how to evaluate a paper. Older scientists draw on years of experience and a solid understanding of basic principles but young students don't have that wisdom.

There are a few tricks one can use to judge the credibility of the authors and one of the most important is whether they address all of the criticisms and problems with their hypotheses. The absence of such self-criticism is a good indicator of incompetence and it's one of the main reasons why the speculations of the ENCODE researchers in 2012 were quickly challenged. The presence of such self-criticism, as in this paper, is not a guarantee of credibility but it helps.

Note: I have to add that I'm a big fan of Bill Martin. We have met on several occasions and corresponded from time to time. Here's a photo of us eating an expensive meal at a fancy restaurant in downtown Toronto.

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