Thermodynamic favorability and pathway yield as evolutionary tradeoffs in biosynthetic pathway choice

Bin Du, Daniel C. Zielinski, Jonathan M. Monk, Bernhard O. Palsson*

*Corresponding author for this work

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The structure of the metabolic network contains myriad organism-specific variations across the tree of life, but the selection basis for pathway choices in different organisms is not well understood. Here, we examined the metabolic capabilities with respect to cofactor use and pathway thermodynamics of all sequenced organisms in the Kyoto Encyclopedia of Genes and Genomes Database. We found that (i) many biomass precursors have alternate synthesis routes that vary substantially in thermodynamic favorability and energy cost, creating tradeoffs that may be subject to selection pressure; (ii) alternative pathways in amino acid synthesis are characteristically distinguished by the use of biosynthetically unnecessary acyl-CoA cleavage; (iii) distinct choices preferring thermodynamic-favorable or cofactor-use-efficient pathways exist widely among organisms; (iv) cofactor-use-efficient pathways tend to have a greater yield advantage under anaerobic conditions specifically; and (v) lysine biosynthesis in particular exhibits temperature-dependent thermodynamics and corresponding differential pathway choice by thermophiles. These findings present a view on the evolution of metabolic network structure that highlights a key role of pathway thermodynamics and cofactor use in determining organism pathway choices.
Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number44
Pages (from-to)11339-11344
Publication statusPublished - 2018


  • Thermodynamics
  • Metabolism
  • Evolution
  • Constraint-based modeling


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