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Existing analyses based on control engineering approaches have not been very explicit about whether metabolic or gene-expression regulation would be involved, but designed different ways in which regulation could be organized, with the potential of causing adaptation to be perfect.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>This study integrates control engineering and classical MCA augmented with supply\u2013demand theory and HCA. Because gene-expression regulation involves time integration, it is identified as a natural instantiation of the \u2018integral control\u2019 (or near integral control) known in control engineering. This study then focuses on robustness against and adaptation to perturbations of process activities in the network, which could result from environmental perturbations, mutations or slow noise. It is shown however that <jats:italic>this<\/jats:italic> type of \u2018integral control\u2019 should rarely be expected to lead to the \u2018perfect adaptation\u2019: although the gene-expression regulation increases the robustness of important metabolite concentrations, it rarely makes them infinitely robust. For perfect adaptation to occur, the protein degradation reactions should be zero order in the concentration of the protein, which may be rare biologically for cells growing steadily.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>A proposed new framework integrating the methodologies of control engineering and metabolic and hierarchical control analysis, improves the understanding of biological systems that are regulated both metabolically and by gene expression. In particular, the new approach enables one to address the issue whether the intracellular biochemical networks that have been and are being identified by genomics and systems biology, correspond to the \u2018perfect\u2019 regulatory structures designed by control engineering vis-\u00e0-vis optimal functions such as robustness. To the extent that they are not, the analyses suggest how they may become so and this in turn should facilitate synthetic biology and metabolic engineering.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-7-131","type":"journal-article","created":{"date-parts":[[2013,11,21]],"date-time":"2013-11-21T16:03:13Z","timestamp":1385049793000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["(Im)Perfect robustness and adaptation of metabolic networks subject to metabolic and gene-expression regulation: marrying control engineering with metabolic control analysis"],"prefix":"10.1186","volume":"7","author":[{"given":"Fei","family":"He","sequence":"first","affiliation":[]},{"given":"Vincent","family":"Fromion","sequence":"additional","affiliation":[]},{"given":"Hans V","family":"Westerhoff","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2013,11,21]]},"reference":[{"key":"1221_CR1","doi-asserted-by":"publisher","first-page":"2166","DOI":"10.1073\/pnas.0509831103","volume":"103","author":"S Rossell","year":"2006","unstructured":"Rossell S, Van Der Weijden CC, Lindenbergh A, van Tuijl A, Francke C, Bakker BM, Westerhoff HV: Unraveling the complexity of flux regulation: a new method demonstrated for nutrient starvation in Saccharomyces cerevisiae. 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