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Protein cost minimization promotes the emergence of coenzyme redundancy

Goldford, Joshua E. and George, Ashish B. and Flamholz, Avi I. and Segrè, Daniel (2021) Protein cost minimization promotes the emergence of coenzyme redundancy. . (Unpublished)

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Coenzymes distribute a variety of chemical moieties throughout cellular metabolism, participating in group (e.g., phosphate, acyl) and electron transfer. For a variety of reactions requiring acceptors or donors of specific resources, there often exist degenerate sets of molecules (e.g., NAD(H) and NADP(H)) that carry out similar functions. Although the physiological roles of various coenzyme systems are well established, it is unclear what selective pressures may have driven the emergence of coenzyme redundancy. Here we use genome-wide metabolic modeling approaches to decompose the selective pressures driving enzymatic specificity for either NAD(H) or NADP(H) in the metabolic network of Escherichia coli. We found that few enzymes are thermodynamically constrained to using a single coenzyme, and in principle, a metabolic network relying on only NAD(H) is feasible. However, structural and sequence analyses revealed widespread conservation of residues that retain selectivity for either NAD(H) or NADP(H), suggesting that additional forces may shape specificity. Using a model accounting for the cost of oxidoreductase enzyme expression, we found that coenzyme redundancy universally reduces the minimal amount of protein required to catalyze coenzyme-coupled reactions, inducing individual reactions to strongly prefer one coenzyme over another when reactions are near thermodynamic equilibrium. We propose that protein minimization generically promotes coenzyme redundancy, and that coenzymes typically thought to exist in a single pool (e.g., CoA) may exist in more than one form (e.g., dephospho-CoA).

Item Type:Report or Paper (Discussion Paper)
Related URLs:
URLURL TypeDescription Paper
Goldford, Joshua E.0000-0001-7315-8018
Flamholz, Avi I.0000-0002-9278-5479
Segrè, Daniel0000-0003-4859-1914
Alternate Title:Thermodynamics drives coenzyme redundancy in metabolism
Additional Information:The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. Version 1: May 18, 2021, 09:42; Version 2: May 18, 2021, 19:42; Version 3: June 17, 2021. We thank Arren Bar-Even, Adrian Jinich, Igor Libourel and Pankaj Mehta for helpful discussions. We acknowledge the support provided by the Directorates for Biological Sciences (BIO) and Geosciences (GEO) at the NSF and NASA under Agreements No. 80NSSC17K0295, 80NSSC17K0296 and 1724150 issued through the Astrobiology Program of the Science Mission Directorate. J.E.G. is supported by the Gordon and Betty Moore Foundation as Physics of Living Systems Fellows through grant number GBMF4513. Author Contributions: J.E.G.. and D.S. designed the research. J.E.G. wrote code and ran simulations. J.E.G. and A.I.F. performed analysis. A.B.G. contributed to protein cost modeling. J.E.G., A.I.F., and D.S. wrote the manuscript. All authors read and approved the final manuscript. The authors declare no competing financial interests.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF4513
Subject Keywords:Metabolism, evolution, coenzymes, constraint-based modeling
Record Number:CaltechAUTHORS:20210524-113358108
Persistent URL:
Official Citation:Protein cost minimization promotes the emergence of coenzyme redundancy. Joshua E. Goldford, Ashish B. George, Avi I. Flamholz, Daniel Segrè. bioRxiv 2021.05.17.444566; doi:
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:109235
Deposited By: George Porter
Deposited On:24 May 2021 21:34
Last Modified:21 Jun 2021 23:00

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