{'fraction_non_alphanumeric': 0.019321148825065273, 'fraction_numerical': 0.0026109660574412533, 'mean_word_length': 5.494915254237288, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Small protein folds at the root of an ancient metabolic network

Significance Life dissipates energy far from thermodynamic equilibrium via electron transport systems that are coupled to external sources of oxidants and reductants. Biological electron transport, in turn, is catalyzed by a suite of enzymes that comprise the superfamily of oxidoreductases. The origin of oxidoreductases is enigmatic. Comparing protein topology and the sequence of modern oxidoreductases, we deduce a putative common ancestor that may have existed at the earliest stages of metabolism. Through duplication, recruitment of other proteins, and diversification, this ancestral protein may have evolved to facilitate electron transfer and redox catalysis at a very early stage in the origin of metabolism. Life on Earth is driven by electron transfer reactions catalyzed by a suite of enzymes that comprise the superfamily of oxidoreductases (Enzyme Classification EC1). Most modern oxidoreductases are complex in their structure and chemistry and must have evolved from a small set of ancient folds. Ancient oxidoreductases from the Archean Eon between ca. 3.5 and 2.5 billion years ago have been long extinct, making it challenging to retrace evolution by sequence-based phylogeny or ancestral sequence reconstruction. However, three-dimensional topologies of proteins change more slowly than sequences. Using comparative structure and sequence profile-profile alignments, we quantify the similarity between proximal cofactor-binding folds and show that they are derived from a common ancestor. We discovered that two recurring folds were central to the origin of metabolism: ferredoxin and Rossmann-like folds. In turn, these two folds likely shared a common ancestor that, through duplication, recruitment, and diversification, evolved to facilitate electron transfer and catalysis at a very early stage in the origin of metabolism.