dorsal/arxiv
View SchemaMetabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control
| Authors | Hong Qian, Daniel A. Beard |
|---|---|
| Categories | |
| ArXiv ID | q-bio/0511005 |
| URL | https://arxiv.org/abs/q-bio/0511005 |
| DOI | 10.1049/ip-syb:20050086 |
| Journal | IEE Proceedings - Systems Biology , Vol. 153, pp. 192-200 (2006) |
Abstract
It has long been hypothesized that futile cycles in cellular metabolism are involved in the regulation of biochemical pathways. Following the work of Newsholme and Crabtree, we develop a quantitative theory for this idea based on open-system thermodynamics and metabolic control analysis. It is shown that the {\it stoichiometric sensitivity} of an intermediary metabolite concentration with respect to changes in steady-state flux is governed by the effective equilibrium constant of the intermediate formation, and the equilibrium can be regulated by a futile cycle. The direction of the shift in the effective equilibrium constant depends on the direction of operation of the futile cycle. High stoichiometric sensitivity corresponds to ultrasensitivity of an intermediate concentration to net flow through a pathway; low stoichiometric sensitivity corresponds to super-robustness of concentration with respect to changes in flux. Both cases potentially play important roles in metabolic regulation. Futile cycles actively shift the effective equilibrium by expending energy; the magnitude of changes in effective equilibria and sensitivities is a function of the amount of energy used by a futile cycle. This proposed mechanism for control by futile cycles works remarkably similarly to kinetic proofreading in biosynthesis. The sensitivity of the system is also intimately related to the rate of concentration fluctuations of intermediate metabolites. The possibly different roles of the two major mechanisms for cellular biochemical regulation, namely reversible chemical modifications via futile cycles and shifting equilibrium by macromolecular binding, are discussed.
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"abstract": "It has long been hypothesized that futile cycles in cellular metabolism are\ninvolved in the regulation of biochemical pathways. Following the work of\nNewsholme and Crabtree, we develop a quantitative theory for this idea based on\nopen-system thermodynamics and metabolic control analysis. It is shown that the\n{\\it stoichiometric sensitivity} of an intermediary metabolite concentration\nwith respect to changes in steady-state flux is governed by the effective\nequilibrium constant of the intermediate formation, and the equilibrium can be\nregulated by a futile cycle. The direction of the shift in the effective\nequilibrium constant depends on the direction of operation of the futile cycle.\nHigh stoichiometric sensitivity corresponds to ultrasensitivity of an\nintermediate concentration to net flow through a pathway; low stoichiometric\nsensitivity corresponds to super-robustness of concentration with respect to\nchanges in flux. Both cases potentially play important roles in metabolic\nregulation. Futile cycles actively shift the effective equilibrium by expending\nenergy; the magnitude of changes in effective equilibria and sensitivities is a\nfunction of the amount of energy used by a futile cycle. This proposed\nmechanism for control by futile cycles works remarkably similarly to kinetic\nproofreading in biosynthesis. The sensitivity of the system is also intimately\nrelated to the rate of concentration fluctuations of intermediate metabolites.\nThe possibly different roles of the two major mechanisms for cellular\nbiochemical regulation, namely reversible chemical modifications via futile\ncycles and shifting equilibrium by macromolecular binding, are discussed.",
"arxiv_id": "q-bio/0511005",
"authors": [
"Hong Qian",
"Daniel A. Beard"
],
"categories": [
"q-bio.SC",
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],
"doi": "10.1049/ip-syb:20050086",
"journal_ref": "IEE Proceedings - Systems Biology , Vol. 153, pp. 192-200 (2006)",
"title": "Metabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control",
"url": "https://arxiv.org/abs/q-bio/0511005"
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