Rosa Rubicondior: Creationism Refuted - How LUCA Got It's Enzymes

Metabolic networks provide clues about the earliest stages of enzyme evolution | Science Tokyo

Metabolic Reactions Reveal Early Enzyme Evolution

One of creationism’s more persistent claims is that evolution cannot produce “new genetic information” because doing so would violate the second law of thermodynamics. The proposed escape from this imaginary prohibition is, inevitably, a supernatural information-provider. But the second law contains no ban on mutations producing new biological functions. It concerns entropy: the total entropy of an isolated system cannot decrease. Living organisms exchange energy and matter with their surroundings, and their activities increase the entropy of those surroundings. Building DNA, growing a leaf and evolving a new enzyme require no suspension of physics. The thermodynamic principles are explained here.

The argument also trades on treating genetic “information” as though it were a mysterious substance that only intelligence can manufacture. Genes are physical sequences of DNA, and those sequences can change, duplicate and recombine. Following duplication, one copy can retain an established function while the other accumulates changes that enable a different or more specialised activity. Natural selection can favour useful variants. A new biological capability need not require an entirely new molecular structure, still less a miraculous delivery of instructions.

This is what makes a study by Tatsuya Corlett and colleagues, published in PNAS, particularly relevant. The researchers combined metabolic-reaction networks with protein-fold data to infer the relative order in which enzyme structures emerged. Their model points to a prominent early role for α/β folds—structures containing both alpha helices and beta sheets—and suggests that most oxygen-using enzymes arose through the adaptation of existing folds as oxygen became available. Evolution could expand its biochemical repertoire by modifying structures already present.

The creationist demand for something wholly unprecedented therefore misses how evolution works. Novelty can reside in a changed activity, a different molecular target or a new regulatory relationship. Retaining an ancestral protein framework does not make a newly evolved function any less new. Nor does calling the result “information” establish a thermodynamic obstacle to its origin.

The research also extends the investigation of our shared biochemical ancestry towards the interval before LUCA, the last universal common ancestor of living organisms. LUCA was not necessarily the first life: its enzymes already had an evolutionary history. These results are model-based historical inferences, rather than recovered pre-LUCA proteins or a direct measurement of increasing genetic information. Nevertheless, they offer a way to investigate that earlier history through the organisation of metabolism itself.

New Genetic Functions, Thermodynamics and Life Before LUCA. How does evolution produce new genetic functions?

Genetic information is embodied in the sequence of DNA and its effects on biological processes. It is not a mysterious substance that must be supplied by an intelligent agent. Mutations, gene duplication and recombination can produce new sequences, while changes in gene regulation can alter when, where and how much a gene is expressed.

Gene duplication provides one route to evolutionary innovation. An additional copy can initially perform the same function as the original. Subsequent mutations can change its activity, and natural selection can favour changes that improve survival or reproduction. Sometimes the copies divide the original gene’s roles between them; sometimes one acquires a different function. Many duplicates are eventually lost.

Consider a hypothetical enzyme that acts efficiently on substance A but also has a weak activity on substance B. Following gene duplication, one copy might retain its activity on A while the other accumulates mutations that improve its activity on B. The organism can thereby acquire a useful biochemical capability without an entirely new protein structure appearing at once.

A protein fold is the basic three-dimensional arrangement of a protein or one of its domains. Related proteins can retain a similar fold while catalysing different reactions. Reusing an ancestral structure therefore does not mean that no new function has evolved.

Why does this not violate the second law of thermodynamics?

The second law states that the total entropy of an isolated system cannot decrease. An isolated system exchanges neither energy nor matter with its surroundings. Organisms are open systems: they take in energy and matter and release heat and waste products.

Cells couple energy-requiring activities, such as building DNA and proteins, to reactions that release usable energy. Local organisation can increase while the total entropy of the organism and its surroundings increases. There is no thermodynamic prohibition on constructing a new DNA sequence or producing a protein with a new activity.

Energy supply alone does not explain adaptation. It makes biological construction and reproduction possible; mutation and recombination generate variation, and natural selection changes the prevalence of heritable variants through differences in reproductive success. These processes have distinct roles, all compatible with thermodynamics.

Nor can genetic “information” simply be substituted for thermodynamic entropy. Information has several technical definitions, and a claim about increasing information must specify what is being measured. Calling a useful genetic change “new information” does not establish that it breaks a physical law.

LUCA was not the beginning of evolution

LUCA means the last universal common ancestor of all living cellular organisms. It refers to an ancestral population from which today’s cellular life inherited shared biological machinery. LUCA should not be confused with the first living thing or necessarily with a single individual.

By LUCA’s time, substantial biochemical evolution had already occurred. The shared genetic code, translation machinery and conserved molecular features provide powerful evidence of common ancestry. However, reconstructing events before LUCA is especially difficult because much earlier history has been lost or obscured.

The enzyme study approaches this problem by combining metabolic dependencies with protein-fold data. Its reconstruction suggests that early metabolism relied heavily on certain structures and that later biochemical capabilities frequently arose through reuse and modification. These are model-based historical inferences, not recovered pre-LUCA proteins. They help investigate an ancient evolutionary history without claiming to have resolved the original emergence of life.

Brief glossary

Gene duplication:

The production of an additional copy of a gene.
Mutation:

A change in a genetic sequence.
Natural selection:

Differences in reproductive success associated with heritable variation.
Protein fold:

The basic three-dimensional arrangement of a protein or protein domain.
Entropy:

A physical quantity related to the number of microscopic arrangements compatible with a system’s overall state.
Open system:

A system that exchanges energy and matter with its surroundings.
LUCA:

The last universal common ancestor of living cellular organisms.
Further reading:
OpenStax: The Laws of Thermodynamics; Institute of Science Tokyo: Metabolic networks provide clues about the earliest stages of enzyme evolution; Corlett and colleagues: The history of enzyme evolution embedded in metabolism.

The broader implication is a picture of biochemical continuity: later capabilities developing from an inherited repertoire of earlier components. That fits common descent and modification, although this study alone does not establish a single origin of life. Its strength lies in making aspects of an extraordinarily ancient history open to scientific investigation. Where creationism invokes an undefined “information” barrier and supplies magic as the answer, researchers are identifying the structures, relationships and evolutionary processes that can explain how biological complexity arose.

The paper in PNAS was accompanied by a press release from the Institute of Science Tokyo:

Metabolic networks provide clues about the earliest stages of enzyme evolution

New model uses metabolic reactions to predict the structures and functions of the earliest enzymes
Enzymes emerged before the last universal common ancestor, making comparative genetic analyses insufficient to understand the earliest stages of enzyme evolution. Researchers at Science Tokyo have combined protein fold structure data and metabolic reaction networks to create a predictive model called enzyme-gated network expansion. The model predicts that the earliest enzymes were predominantly α/β folds, suggesting that the origin of enzyme-mediated metabolic reactions may have been sparked by a single enzyme structure type.
Background

The enzymes we see in modern organisms are complex proteins, often with multiple folded sub-structures and specialized catalytic sites. As we know, proteins are coded by genes. If we trace the history of enzymes across all living creatures using comparisons of genes, it brings us to the last universal common ancestor (LUCA), a hypothetical organism that existed around 4 billion years ago and is believed to be the ancestor of lifeforms on Earth.

However, even the LUCA’s proteins must have been complex to run the core machinery of a living cell. Because comparative analyses will not help us understand how proteins evolved before the LUCA emerged, alternative approaches are needed to reveal the earliest enzymes. One possible alternative is to look at the evolution of enzymes that catalyze metabolic reactions, which includes the breakdown of molecules in the cell to extract energy and the synthesis of complex metabolites. Metabolic reactions are layered, meaning the end product of one reaction becomes the raw material for another, resulting in a complex web. “Emphasizing the layered structure of metabolism has produced significant insights into the chemistry of primitive metabolic systems and the environment of the earliest life. Here, we use this approach to study the evolution of the first enzymes,” notes Dr. Liam M. Longo, Specially Appointed Associate Professor from the Earth-Life Science Institute (ELSI), Institute of Science Tokyo (Science Tokyo), Japan.

Longo and Specially Appointed Associate Professor Harrison B. Smith, together with doctoral student Tatsuya Corlett, both from ELSI at Science Tokyo, led an international research effort to reconstruct the history of enzymes based on the layers of metabolism. Their findings were made available online on August 11, 2026, and were published in Volume 123, Issue 33 of the journal Proceedings of the National Academy of Sciences on August 18, 2026.

Results

Longo’s team first turned to large databases of metabolic reactions and protein structures. Using a model of metabolic evolution based on biochemical data from the Kyoto Encyclopedia of Genes and Genomes, they identified 4,294 metabolites and 7,678 reactions mediated by 4,331 enzymes and their variants. From the Evolutionary Classification of Domains database, they identified 396 metabolic protein folds that each adopt one of six structure types.

With this data as the foundation, the team developed a model of metabolic layering starting from simple molecules that were believed to exist on Earth before the LUCA. They used the reactions associated with simple compounds at the heart of metabolism to infer which enzymes may have been present at the earliest stages of metabolic evolution. They called this model “enzyme-gated network expansion.”

This model produced multiple interesting results. First, most early enzymes created by the model had α/β structures, whereas enzymes in all modern organisms and the LUCA include α alone, β alone, as well as mixtures of these elements. This finding showed that α/β catalytic sites could have driven many early metabolic reactions.
The outsized role of α/β proteins in metabolism may relate to their special ability to bind phosphate, which is a key component of many cofactors.

Liam M. Longo, co-corresponding author.
Earth-Life Science Institute
Institute of Science Tokyo
Tokyo, Japan.

The team then looked at a major transformative event in evolutionary history—photosynthesis, which introduced large amounts of oxygen into a largely anaerobic atmosphere. Did entirely new enzymes evolve in response to this new metabolic environment? Some new enzymes did emerge, but most oxygen-metabolizing enzymes were adapted variants of enzymes that already existed, highlighting the importance of re-functionalization in enzyme evolution.

What do these findings mean for our understanding of protein evolution on a primitive Earth? The model tells us the likely structures of the very first enzymes, and the relative versatility or specialization of different fold structures. Combining this approach with comparative studies of highly conserved structures like ribosomes could tell us more about enzymes and metabolic evolution.

This work is a key step toward building an integrated history of protein evolution, where enzymes, cofactors, and metabolic reactions are considered.

Tatsuya Corlett, first author.
Earth-Life Science Institute
Institute of Science Tokyo
Tokyo, Japan.

Publication:
T. Corlett, H.B. Smith, E. Smith, J.E. Goldford, & L.M. Longo
The history of enzyme evolution embedded in metabolism
Proc. Natl. Acad. Sci. U.S.A. 123(33) e2609531123, https://doi.org/10.1073/pnas.2609531123 (2026).

Significance
Enzyme emergence is an ongoing process that began ~4 billion years ago. Here, we show that the modern biosphere-scale network of metabolic reactions and enzymes is an archive of enzyme history independent from, but concordant with, phylogenetics. Based on this record, we predict the order of enzyme emergence from before the last universal common ancestor up until the biological production and metabolic utilization of molecular oxygen. We find that while α/β proteins dominated primitive enzyme-mediated metabolism, other folds—including the cradle-loop barrel, which is a member of the small β-barrel metafold—were likely important early contributors. This study represents key progress toward building an internally consistent, joint history of metabolic reactions and enzymes.

Abstract
Whereas phylogenetic reconstructions are a primary record of protein evolution, it is unknown whether the deep history of enzymes is encoded at higher levels of biological organization. Here, we demonstrate that the emergence and reuse history of enzymatic folds is embedded within the web of metabolite-cofactor-enzyme interdependencies that comprise biosphere-scale metabolic reaction networks. Using a simple network analysis approach, we reconstruct the relative ordering of enzymatic fold emergence and, where possible, the first reaction(s) that each enzymatic fold catalyzed. We find that a large majority of enzymatic folds were sufficient as independent additions to open new avenues for metabolic growth. The resulting network-based histories are broadly concordant with enzyme phyletic distribution in prokaryotes, a proxy for enzyme age. Our results suggest that the earliest enzyme-mediated metabolisms were enriched for α/β proteins, likely due to their strong association with cofactor utilization, and that α-proteins preferentially emerge at later stages. The cradle-loop barrel, a member of the small β-barrel metafold, is predicted to be the founding β-fold, in agreement with analyses of ribosome structure. An examination of how the protein universe responded to the biological production of molecular oxygen reveals that the adaptation of existing enzymatic folds, not novel fold emergence, was the primary driver of metabolic evolution. This work presents a self-consistent model of metabolic and enzyme evolution, key progress toward integrating diverse perspectives into a unified history of protein evolution.

T. Corlett, H.B. Smith, E. Smith, J.E. Goldford, & L.M. Longo
The history of enzyme evolution embedded in metabolism
Proc. Natl. Acad. Sci. U.S.A. 123(33) e2609531123, https://doi.org/10.1073/pnas.2609531123 (2026).

Copyright: © 2026 The authors.
Published by National Academy of Science of the USA. Open access.
Reprinted under a Creative Commons Attribution 4.0 International license (CC BY 4.0)

The picture emerging from this research is one of evolution building on what already existed. As new metabolic opportunities arose, existing protein structures could acquire new functions through modification. Biochemical novelty did not require every enzyme to be invented from scratch, let alone a supernatural agent supplying additional “information”. The model instead points to the importance of inherited structures being adapted to different tasks—the sort of historical continuity that common descent leads us to expect.

The creationist appeal to the second law of thermodynamics contributes nothing to explaining this history. That law does not prohibit genetic change, new enzyme activities or increasing biological complexity in organisms exchanging energy and matter with their surroundings. Calling these changes “new information” does not make them thermodynamically forbidden. The supposed need for a miraculous information-provider arises from misrepresenting physics, not from a discovery in biology.

There are, of course, limits to what this study establishes. Its reconstruction of early enzyme evolution is a model-based inference, not a collection of proteins recovered from before LUCA. Nor does it settle how life first arose. Its significance is that it provides a framework for investigating an otherwise elusive period, using relationships among metabolic reactions and protein structures that remain accessible to research. Uncertainty becomes a question to investigate, with assumptions and predictions open to scrutiny.

Common ancestry and evolutionary modification are therefore central to making sense of the findings. The biochemical machinery of living organisms preserves traces of a history extending beyond their last universal common ancestor. Science is finding ways to examine those traces. Creationism’s insistence that natural processes cannot produce novelty offers no comparable explanation—and invoking magic does nothing to remedy that failure.

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