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Although flux optimization is widely recognized as a central objective of metabolic networks, how flux efficiency influences the allocation of the metabolic proteome remains unclear and lacks direct validation. Here, we derive a simple analytical relationship linking the equilibrium constant (K) and the catalytic-abundance quotient (CAQ) of reactions within a pathway that defines the condition for maximal efficiency. By integrating reaction thermodynamics, enzyme kinetics, transcriptomic, and proteomic data, we compared enzyme allocation in glycolysis and the TCA cycle with this K-CAQ relationship across evolutionarily distant species, and showed that deviation from it can be explained by a trade-off between maximizing flux efficiency and concentrating flux control. Moreover, the drive to optimize glycolytic efficiency is strengthened under oncogenic signaling and a limited cellular budget for glycolytic enzymes. These findings establish a principle of Pareto optimality governing enzyme allocation in metabolic pathways and reveal key determinants of efficiency optimality in glycolysis.<\/jats:p>","DOI":"10.1038\/s44320-026-00250-5","type":"journal-article","created":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:42:05Z","timestamp":1791074525000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Trade-off between flux efficiency and metabolic control shapes enzyme allocation"],"prefix":"10.1038","author":[{"given":"Kai","family":"Sun","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyan","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4238-9816","authenticated-orcid":false,"given":"Wenchao","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyun","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0858-638X","authenticated-orcid":false,"given":"Ziwei","family":"Dai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,4]]},"reference":[{"key":"250_CR1","doi-asserted-by":"publisher","first-page":"3695","DOI":"10.1073\/pnas.062526999","volume":"99","author":"H Akashi","year":"2002","unstructured":"Akashi H, Gojobori T (2002) Metabolic efficiency and amino acid composition in the proteomes of Escherichia coli and Bacillus subtilis. 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