Rethinking glycolysis: On the biochemical logic of metabolic pathways

Arren Bar-Even, Avi Flamholz, Elad Noor, Ron Milo

Research output: Contribution to journalReview articlepeer-review

148 Scopus citations


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.

Original languageEnglish
Pages (from-to)509-517
Number of pages9
JournalNature Chemical Biology
Issue number6
StatePublished - 1 Jan 2012
Externally publishedYes


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