Papp´s talk highlights (Session 2)
“How do new metabolic pathways evolve? According to the most accepted paradigm, new pathways are patched together from preexisting enzymes borrowed from different parts of the network. Central to this ‘patchwork’ model of pathway evolution is the notion that many enzymes have limited substrate specificities and can catalyze, albeit at low rates, reactions other than those for which they have evolved. These so-called underground or side activities are prevalent and were shown to serve as starting points for the evolution of novel functions both in directed evolution experiments and in the diversification of gene families in the wild. However, how the underground catalytic repertoire encoded in the genome could operate within the context of the existing network to generate novelties remains unknown. Do underground reactions remain isolated or can they be wired into the native network and endow it with novel capabilities? How does enzyme chemistry constrain the network position of underground reactions and why aren’t they part of native, evolved, pathways? To explore these issues, we manually compiled previously reported side activities of E. coli enzymes and integrated these reactions into a global metabolic reconstruction of the same organism. Due to chemical constraints, these side reactions are non-randomly distributed, and half of them can be wired into the native metabolic network. They generally contribute to novel metabolic pathways with important end-products, underscoring their potential biological relevance at the network level. However, we identified two factors that might limit the evolution of these novel pathways in nature. First, underground reactions tend to introduce toxic metabolites into the network. Second, despite their seamless integration into the network, most underground activities do not confer an advantage in any of a wide range of nutrient conditions. We conclude that a large fraction of the biochemically feasible raw material have remained unexploited by adaptive evolution”.