Decoupling of global metabolic flux and proteome partitioning in bacteria
- Ryan Thiermann
- Jin Yang
- Aniket Zodage
- Fukang She
- Danny K. Fung
- Taylor Rytlewski
- Farshad Abdollah-Nia
- Fangzhou Xiao
- John T. Sauls
- Sarah Cox
- Zulfar Ghulam-Jelani
- Victoria Castillo
- Quinn A. Paulsen
- David M. Stevenson
- Daniel Amador-Noguez
- James R. Williamson
- Jue D. Wang
- Suckjoon Jun
2026-06-18
Bacteria regulate homeostatic growth by adjusting proteome composition. In Escherichia coli , this coordination is mediated by guanosine tetraphosphate and pentaphosphate, collectively termed (p)ppGpp, which couple amino acid supply with ribsosome production. We identified a distinct architecture in Bacillus subtilis , in which guanosine triphosphate (GTP), not (p)ppGpp, controls proteome allocation. Translational inhibition resulted in GTP depletion and suppressed amino acid biosynthesis through feedback inhibition without altering ribosome abundance, establishing a regulated decoupling between total amino acid flux and proteome composition, with flux deviating from proteome-based predictions. By artificially adjusting GTP concentrations, we recoupled flux and proteome, restoring growth to maximal amounts. The regulated suboptimality enables a trade-off to balance growth and stress resilience. Similar GTP-based strategies were present in other Firmicute species, indicating possible evolutionary conservation. Proteome composition and metabolic flux have distinct regulatory layers in some bacteria.