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Abstract The core metabolic reactions of life drive electrons through a class of redox protein enzymes, the oxidoreductases. The energetics of electron flow is determined by the redox potentials of organic and inorganic cofactors as tuned by the protein environment. Understanding how protein structure affects oxidation–reduction energetics is crucial for studying metabolism, creating bioelectronic systems, and tracing the history of biological energy utilization on Earth. We constructed ProtReDox (https://protein-redox-potential.web.app), a manually curated database of experimentally determined redox potentials. With over 500 measurements, we can begin to identify how proteins modulate oxidation–reduction energetics across the tree of life. By mapping redox potentials onto networks of oxidoreductase fold evolution, we can infer the evolution of electron transfer energetics over deep time. ProtReDox is designed to include user‐contributed submissions with the intention of making it a valuable resource for researchers in this field.
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This content will become publicly available on August 7, 2026
On the emergence of metabolism: the evolution of proteins that powered life
Life is far from thermodynamic equilibrium. Hence, life must extract energy from the environment. On Earth, that energy is driven by networks of metabolic reactions in all cells which ultimately move electrons and protons (i.e. hydrogen atoms) across the planet. The origin of metabolism required the emergence and evolution of proteins. Proteins are nanometre-scale chemical machines—i.e. literal nanomachines which physically move. These nanomachines enable living systems to perform essential biochemical tasks from replication to metabolism; the latter being the engines of life. In all extant life on Earth, a small set of these nanomachines, called oxidoreductases, couple chemical energy from the environment with core redox reactions including photosynthesis, respiration and nitrogen fixation. The origins and emergence of complex life have been intimately tied with evolution of oxidoreductases. Here, using structure-based analyses, we describe the evolution of the protein catalysts in three biological epochs. First, thermodynamically driven polymerization reactions generated simple metal-binding peptides with specific sequences that catalysed core metabolic reactions. Second, these catalysts were incorporated in small structural ‘folds’. In the third epoch, these folds served as building blocks for extant, complex nanomachines. This article is part of the discussion meeting issue ‘Chance and purpose in the evolution of biospheres’.
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- Award ID(s):
- 2025200
- PAR ID:
- 10648408
- Publisher / Repository:
- Royal Society
- Date Published:
- Journal Name:
- Philosophical Transactions of the Royal Society B: Biological Sciences
- Volume:
- 380
- Issue:
- 1931
- ISSN:
- 0962-8436
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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