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Rethinking glycolysis: on the biochemical logic of metabolic pathways

Abstract

Metabolic pathways may seem arbitrary and unnecessarily complex. In many cases, a chemist might devise a simpler route for the biochemical transformation, so why has nature chosen such complex solutions? In this review, we distill lessons from a century of metabolic research and introduce new observations suggesting that the intricate structure of metabolic pathways can be explained by a small set of biochemical principles. Using glycolysis as an example, we demonstrate how three key biochemical constraints—thermodynamic favorability, availability of enzymatic mechanisms and the physicochemical properties of pathway intermediates—eliminate otherwise plausible metabolic strategies. Considering these constraints, glycolysis contains no unnecessary steps and represents one of the very few pathway structures that meet cellular demands. The analysis presented here can be applied to metabolic engineering efforts for the rational design of pathways that produce a desired product while satisfying biochemical constraints.

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Figure 1: The Embden-Meyerhof-Parnas glycolytic pathway.
Figure 2: The reduction potentials, E′, of half-reactions between functional groups composed of only carbon, oxygen and hydrogen.
Figure 3: Sequential assembly of the lower glycolytic reaction sequence according to biochemical constraints: the basic energetic and mechanistic constraints.
Figure 4: Sequential assembly of the glycolytic reaction sequence according to biochemical constraints: redox carriers, feasible mechanisms and energy conservation.
Figure 5: Proposed pathways for the production of 3-hydroxypropionate from pyruvate.

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Acknowledgements

We thank D. Tawfik for helpful discussions, scientific support and critique regarding the manuscript. We also would like to thank D. Arlow, R. Burton, D. Fraenkel, R. Last, W. Liebermeister, A. Weber and members of the Milo laboratory for helpful comments. A.B.-E. is supported by the Adams Fellowship Program of the Israel Academy of Sciences and Humanities. E.N. is grateful to the Azrieli Foundation for the award of an Azrieli Fellowship. This study was supported by the European Research Council (grant 260392–SYMPAC) and by the Israel Science Foundation (Grant 750/09).

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Bar-Even, A., Flamholz, A., Noor, E. et al. Rethinking glycolysis: on the biochemical logic of metabolic pathways. Nat Chem Biol 8, 509–517 (2012). https://doi.org/10.1038/nchembio.971

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