A Combined Chemoinformatics/Bioinformatics Investigation Of Oxygen Impact On Metabolic Evolution

In the history of biological and geochemical evolution, oxygen rise is a critical event. Some crucial evolutionary steps were linked to the elevated atmospheric oxygen. However, the underlying mechanisms remain elusive. Recently, Raymond and Segre revealed that molecular oxygen allows 1000 more metabolic reactions than can occur in anoxic conditions, which provided important new clues to understanding the correlation between oxygen and evolution. But it is still challenging to find a molecular-level explanation to the link between the increased organism complexity and the elevated oxygen concentration. To investigate the impact of oxygen on evolution, a comprehensive comparative analysis on chemical and biological aspects of anaerobic and aerobic metabolisms was performed by combinatorially using chemoinformatics and bioinformatics approaches.The results clearly indicated that oxygen had exerted a great impact on metabolic evolution. First, oxygen could induce the production of some reactants (e.g., sulphonates and sulphites) that are excluded in anaerobic environments. Second, oxygenation could introduce some novel reaction types (e.g., oxygen-dependent hydroxylation) into metabolism, which enhances the polarity of metabolites. Third, oxygen-dependent reactions do not start from the center of anoxic metabolic network, but from its periphery, which makes the starting points of oxic metabolic reactions rather different from those of anoxic counterparts. However, the diversity and redundancy of oxic metabolites are very similar to those of anoxic compounds, which is a result of the fact that both oxic and anoxic networks are organized by similar hierarchical architectures. Fourth, oxygen could facilitate the generation and prevalence of some cofactors, such as copper ions, NADP(H) and iron (including heme). As a result, oxygen has greatly helped organisms to explore a wider structural and chemical space. To adapt to these biochemical changes evoked by oxygen, the enzymes were driven to recruit new architectures (folds) and catalytic residues. Therefore, the influences of oxygen on metabolic evolution are rather complicated.The oxygen-induced expansion of structural and chemical space of metabolites has some implications for understanding the link between oxygen elevation and organism complexity rise. First, the invention of steroids by oxygen played a crucial role in transmembrane export and import processes of unicellular and multicellular eukaryotes. Second, since oxic metabolism starts from strong hydrophobic substrates, oxic metabolites are more hydrophobic than anoxic compounds on average, which implies that the former are more ready than anoxic compounds to pass through membranes to serve as nuclear receptor ligands. This hypothesis is validated by the observation that most (97.5%) nuclear receptor ligands are produced by aerobic metabolism. Since nuclear signaling system is critical to complex organisms, biological evolution must benefit from aerobic metabolism.The oxygen-induced big innovations in enzyme architectures and functions have some implications for determining the time of oxygen rise. Through identifying the enzyme architectures (folds) innovated for aerobic metabolism and placing them in a protein fold clock, we infer that aerobic metabolism appeared-2.9 billions years ago and that oxygen increased from 0.1% to 1% PAL during a period of -400 million years. This finding supports the early and slow rise of oxygen and suggests that protein folds could serve as an alternative molecular clock for timing ancient evolutionary events, especially those lacking fossil records.These findings not only provide significant clues to determining the time of oxygen rise and understanding the link between oxygen and evolution, but also show the importance of biological small molecules in addressing some basic biological questions. Thus, it is suggested that enough attention should be given to small molecule-based information mining. In this discipline, chemoinformatics will find important use.