Oxidoreductases are a diverse class of enzymes that catalyze electron transfer reactions. In essence, these enzymes drive the energy and metabolism pathways that exist in all domains of life. A Rutgers University-led team of researchers have now narrowed down the entire lineage of life’s oxidoreductases into just four core building blocks that functionally resemble Legos.
For their analyses, the team collected proteomic data from 9,500 3D protein structures within the RCSB Protein Data Bank, which is based in Rutgers. They then used a comparative structural analysis approach to identify a set of of fundamental electron transfer modules with metal-containing cofactors.
As described in their recent paper in the Proceedings of the National Academy of Sciences, the team was able to cluster cofactor microenvironments into the four major modules: bacterial ferredoxin, cytochrome c, symerythrin, and plastocyanin-type folds. These electron transfer modules, the team believes, likely evolved through repeated duplication and diversification to form the oxidoreductases that we know today.
"We don't have a fossil record of what proteins looked like 4 billion years ago, so we have to take what we have today and start walking backwards, trying to imagine what these proteins looked like," said senior author Vikas Nanda. “The study is the first time we've been able to take something with thousands of amino acids and break it down into reasonable chunks that could have had primordial origins."
Insight into the building blocks that lead to the formation of proteins could lead to further applications of biomedical engineering, therapeutic proteins and even forms of biological industrial catalysts.
"Understanding these parts and how they are connected to each other within the existing proteins could help us understand how to design new catalysts that could potentially split water, fix nitrogen or do other things that are really important for society," said co-author Paul Falkowski.
Image: A small set of simple protein building blocks (left) that existed early in evolutionary history likely assembled and repurposed over time to develop into more complex proteins (right). Image courtesy of Vikas Nanda/Rutgers Robert Wood Johnson Medical School.