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Despite such progress, system-level description of the methylotrophic metabolism is currently lacking, and much remains to understand regarding the network-scale organization and properties of methylotrophy, and how the methylotrophic capacity emerges from this organization, especially in facultative organisms.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In this work, we report on the integrated, system-level investigation of the metabolic network of the facultative methylotroph<jats:italic>Methylobacterium extorquens<\/jats:italic>AM1, a valuable model of methylotrophic bacteria. The genome-scale metabolic network of the bacterium was reconstructed and contains 1139 reactions and 977 metabolites. The sub-network operating upon methylotrophic growth was identified from both<jats:italic>in silico<\/jats:italic>and experimental investigations, and<jats:sup>13<\/jats:sup>C-fluxomics was applied to measure the distribution of metabolic fluxes under such conditions. The core metabolism has a highly unusual topology, in which the unique enzymes that catalyse the key steps of C1 assimilation are tightly connected by several, large metabolic cycles (serine cycle, ethylmalonyl-CoA pathway, TCA cycle, anaplerotic processes). The entire set of reactions must operate as a unique process to achieve C1 assimilation, but was shown to be structurally fragile based on network analysis. This observation suggests that in nature a strong pressure of selection must exist to maintain the methylotrophic capability. Nevertheless, substantial substrate cycling could be measured within C2\/C3\/C4 inter-conversions, indicating that the metabolic network is highly versatile around a flexible backbone of central reactions that allows rapid switching to multi-carbon sources.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>This work emphasizes that the metabolism of<jats:italic>M. extorquens<\/jats:italic>AM1 is adapted to its lifestyle not only in terms of enzymatic equipment, but also in terms of network-level structure and regulation. It suggests that the metabolism of the bacterium has evolved both structurally and functionally to an efficient but transitory utilization of methanol. Besides, this work provides a basis for metabolic engineering to convert methanol into value-added products.<\/jats:p><\/jats:sec>","DOI":"10.1186\/1752-0509-5-189","type":"journal-article","created":{"date-parts":[[2011,12,2]],"date-time":"2011-12-02T04:56:17Z","timestamp":1322801777000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":132,"title":["Genome-scale reconstruction and system level investigation of the metabolic network of Methylobacterium extorquensAM1"],"prefix":"10.1186","volume":"5","author":[{"given":"R\u00e9mi","family":"Peyraud","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathrin","family":"Schneider","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Kiefer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"St\u00e9phane","family":"Massou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A","family":"Vorholt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Charles","family":"Portais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,11,10]]},"reference":[{"key":"782_CR1","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1016\/j.tibtech.2008.10.009","volume":"27","author":"J Schrader","year":"2009","unstructured":"Schrader J, Schilling M, Holtmann D, Sell D, Filho MV, Marx A, Vorholt JA: Methanol-based industrial biotechnology: current status and future perspectives of methylotrophic bacteria. 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