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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 (2022) Protein cost minimization promotes the emergence of coenzyme redundancy. Proceedings of the National Academy of Sciences, 119 (14). Art. No. e2110787119. ISSN 0027-8424. doi:10.1073/pnas.2110787119.

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Coenzymes distribute a variety of chemical moieties throughout cellular metabolism, participating in group (e.g., phosphate and 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., coenzyme A [CoA]) may exist in more than one form (e.g., dephospho-CoA).

Item Type:Article
Related URLs:
URLURL TypeDescription Paper ItemCode
Goldford, Joshua E.0000-0001-7315-8018
George, Ashish B.0000-0002-6923-3596
Flamholz, Avi I.0000-0002-9278-5479
Segrè, Daniel0000-0003-4859-1914
Alternate Title:Thermodynamics drives coenzyme redundancy in metabolism
Additional Information:© 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). Published March 28, 2022. We thank Adrian Jinich, Igor Libourel, Pankaj Mehta, and Gina Mawla for helpful discussions, and wish to acknowledge inspiring conversations with Arren Bar-Even, who sadly passed away prematurely. We acknowledge the support provided by the Directorates for Biological Sciences (BIO) and Geosciences (GEO) at the NSF and NASA under agreements 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 a Physics of Living Systems Fellow through grant GBMF4513. D.S. also acknowledges funding from the US Department of Energy, Office of Science, Office of Biological & Environmental Research through the Microbial Community Analysis and Functional Evaluation in Soils Science Focus Area Program (m-CAFEs) under contract number DE-AC02-05CH11231 to Lawrence Berkeley National Laboratory, from the NSF Center for Chemical Currencies of a Microbial Planet (CCoMP, publication #005), and from the NIH National Institute on Aging, award number UH2AG064704. The authors declare no competing interest. This article contains supporting information online at 2110787119/-/DCSupplemental. Data Availability: Code and data have been deposited in GitHub ( All other study data are included in the article and/or supporting information.
Funding AgencyGrant Number
Gordon and Betty Moore FoundationGBMF4513
Department of Energy (DOE)DE-AC02-05CH11231
Subject Keywords:metabolism; evolution; coenzymes; constraint-based modeling
Issue or Number:14
Record Number:CaltechAUTHORS:20210524-113358108
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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:28 Mar 2022 23:19

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