Small protein folds at the root of an ancient metabolic network

Hagai Raanan ^1,5 Saroj Poudel ^1,3 Douglas H. Pike ² Vikas Nanda ² Paul G. Falkowski ^1,3,4

¹Department of Marine and Coastal Sciences, Rutgers University, Environmental Biophysics and Molecular Ecology Program, USA
²Rutgers University, Center for Advanced Biotechnology and Medicine, USA
³Rutgers University, Institute of Earth, Ocean, and Atmospheric Sciences, USA
⁴Rutgers University, Department of Earth and Planetary Sciences, USA
⁵Hebrew University, Department of Plant and Environmental Sciences, Israel

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, are 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 alignments, we quantify the similarity between proximal cofactor-binding folds and show they are derived from a common ancestor. 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.