The quantitative metabolome is shaped by abiotic constraints

Funding Information: We thank Jared Broddrick’s for his valuable comments on the manuscript. We would like to thank Sharon Grubner and Jonathan Hsu. This work was funded by the Novo Nordisk Foundation (Grant Number NNF10CC1016517), the National Institutes of Health (Grant Number GM057089), and the Institute for Systems Biology’s Translational Research Fellows Program (J.T.Y.). Publisher Copyright: © 2021, The Author(s). ; Living systems formed and evolved under constraints that govern their interactions with the inorganic world. These interactions are definable using basic physico-chemical principles. Here, we formulate a comprehensive set of ten governing abiotic constraints that define possible quantitative metabolomes. We apply these constraints to a metabolic network of Escherichia coli that represents 90% of its metabolome. We show that the quantitative metabolomes allowed by the abiotic constraints are consistent with metabolomic and isotope-labeling data. We find that: (i) abiotic constraints drive the evolution of high-affinity phosphate transporters; (ii) Charge-, hydrogen- and magnesium-related constraints underlie transcriptional regulatory responses to osmotic stress; and (iii) hydrogen-ion and charge imbalance underlie transcriptional regulatory responses to acid stress. Thus, quantifying the constraints that the inorganic world imposes on living systems provides insights into their key characteristics, helps understand the outcomes of evolutionary adaptation, and should be considered as a fundamental part of theoretical biology and for understanding the constraints on evolution. ; Peer reviewed