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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“…The aim is to ensure the highest possible effectivity/fluxes on the one hand and to enable the highest possible energy/ATP yields on the other hand. These purposes are achieved under the consideration of chemical and mechanistic feasibilities as well as the physicochemical properties of intermediates with respect to, e.g., stability, permeability, polarity, and toxicity (16,38).…”

Unique Metabolic Features of Stem Cells, Cardiomyocytes, and Their Progenitors

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