Imposing multireaction dependencies provides an innovative strategy to alter metabolic functions

Imposing multireaction dependencies provides an innovative strategy to alter metabolic functions | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Imposing multireaction dependencies provides an innovative strategy to alter metabolic functions Anika Küken, Damoun Langary, Angela Angeleska, Zoran Nikoloski This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6304455/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 23 Oct, 2025 Read the published version in npj Systems Biology and Applications → Version 1 posted 9 You are reading this latest preprint version Abstract Metabolism operates under physico-chemical constraints that result in multireaction dependencies. Understanding how multireaction dependencies affect metabolic phenotypes remains challenging, hindering their biotechnological applications. Here, we propose the concept of a forcedly balanced complex that allows to efficiently determine the effects of specific multireaction dependencies on metabolic network functions. Using this concept, we found that the fraction of multireaction dependencies induced by forcedly balanced complexes in metabolic networks followed power law with exponential cut-off. We identified forcedly balanced complexes that are lethal in cancer but have little effect on growth in healthy tissue models. In addition, these forcedly balanced complexes are largely specific to particular cancer types. Therefore, multireaction dependencies resulting from forced balancing of complexes represent an innovative means to control cancers that, we argue, can be implemented via transporter engineering. The presented constraint-based approaches pave the way for using multireaction dependencies in metabolic engineering for diverse biotechnological applications. Biological sciences/Systems biology/Biochemical networks Biological sciences/Systems biology/Computer modelling Biological sciences/Systems biology/Metabolic engineering Metabolic networks balancing constraint-based modeling metabolic engineering cancer metabolism Full Text Additional Declarations No competing interests reported. Supplementary Files SupplementaryFigures.pdf SupplementaryTableS1.xlsx SupplementaryTableS2.xlsx SupplementaryTableS3.xlsx SupplementaryTableS4.xlsx Cite Share Download PDF Status: Published Journal Publication published 23 Oct, 2025 Read the published version in npj Systems Biology and Applications → Version 1 posted Editorial decision: Revision requested 20 Apr, 2025 Reviews received at journal 19 Apr, 2025 Reviews received at journal 14 Apr, 2025 Reviewers agreed at journal 04 Apr, 2025 Reviewers agreed at journal 01 Apr, 2025 Reviewers invited by journal 27 Mar, 2025 Editor assigned by journal 26 Mar, 2025 Submission checks completed at journal 26 Mar, 2025 First submitted to journal 25 Mar, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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