The proteome is a terminal electron acceptor
Creators
Abstract
Microbial metabolism is impressively flexible, enabling growth even when available nutrients differ greatly from biomass in redox state. Escherichia coli, for example, rearranges its physiology to grow on reduced and oxidized carbon sources through several forms of fermentation and respiration. To understand the limits on and evolutionary consequences of this metabolic flexibility, we developed a coarse-grained mathematical framework coupling redox chemistry with principles of cellular resource allocation. Our models inherit key qualities from both of their antecedents: i) describing diverse metabolic chemistries and ii) enforcing the simultaneous balancing of atom (e.g., carbon), electron, and energy (adenosine triphosphate) flows, as in redox models, while iii) treating biomass as both the product and catalyst of the growth process, as in resource allocation models. Assembling integrated models of respiration, fermentation, and photosynthesis clarified key microbiological phenomena, including demonstrating that autotrophs grow more slowly than heterotrophs because of constraints imposed by the intracellular production of reduced carbon. Our model further predicted that heterotrophic growth is improved by matching the redox state of biomass to the nutrient environment. Through analysis of ≈60,000 genomes and diverse proteomic datasets, we found evidence that proteins indeed accumulate amino acid substitutions promoting redox matching. We therefore propose an unexpected mode of genome evolution where substitutions neutral or even deleterious to the individual biochemical or structural functions of proteins can nonetheless be selected due to a redox-chemical benefit to the population.
Copyright and License
Acknowledgement
Data Availability
Source code for models and analyses are available on GitHub (https://github.com/flamholz/redox-proteome) (97). All other data are included in the manuscript and/or supporting information.
Contributions
A.I.F., A.G., W.W.F., D.K.N., and R.P. designed research; A.I.F. and A.G. performed research; A.I.F. and A.G. contributed new reagents/analytic tools; A.I.F. and A.G. analyzed data; and A.I.F., A.G., W.W.F., D.K.N., and R.P. wrote the paper.
Supplemental Material
Appendix 01 (PDF)
Dataset S01 (XLSX)
Dataset S02 (XLSX)
Dataset S03 (XLSX)
Dataset S04 (XLSX)
Dataset S05 (XLSX)
Dataset S06 (XLSX)
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flamholz-et-al-the-proteome-is-a-terminal-electron-acceptor.pdf
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Additional details
Identifiers
- PMCID
- PMC11725909
Related works
- Describes
- Journal Article: PMC11725909 (PMCID)
- Is new version of
- Discussion Paper: 10.1101/2024.01.31.578293 (DOI)
- Is supplemented by
- Software: https://github.com/flamholz/redox-proteome (URL)
- Software: 10.5281/zenodo.14427140 (DOI)
Funding
- National Science Foundation
- PHY-1748958
- Jane Coffin Childs Memorial Fund for Medical Research
- 61-1772
- Burroughs Wellcome Fund
- Government of India
- Ramalingaswami Fellowship
- Gordon and Betty Moore Foundation
- GBMF4513
- California Institute of Technology
- Caltech Center for Evolutionary Science
- National Institutes of Health
- 1R01AI127850-01A1
- California Institute of Technology
- Donna and Benjamin M. Rosen Bioengineering Center
- National Institutes of Health
- 1R35 GM118043
Dates
- Accepted
-
2024-10-30
- Available
-
2025-01-03Published online