Small molecules as products of evolution

Abstract

The functional evolution of ancient proteins has recently been reconstructed using molecular phylogeny, and the activity of the deduced molecules can be tested. Unfortunately, the world of small molecules escapes such 'resurrection' studies, which rely on ancestral sequence reconstruction. These studies implicitly assume that only the proteins evolve, whereas the small molecules are presumed to be identical now and in the past. Recent evolutionary analysis of biochemical pathways, however, as well as the impressive surge of metabolomics are changing this situation, and it is becoming possible to reconstruct ancient biochemical pathways. We can now begin to infer the chemical structures of key molecules that were present in the past, synthesize those molecules, and test their ability to interact with their cognate (ancient) protein partners. In this essay, we discuss the possibilities offered by these new methodological developments and provide key examples. We also highlight four principles that are important to consider when studying the evolution of small molecules: catalytic promiscuity, metabolic reconfiguration, coevolution and bidirectional interactions. These new developments call for an alliance between organic chemists and evolutionary scientists to investigate the diversity of the chemical building blocks of life, and the evolution of their biosynthetic pathways.