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Although overflow metabolism has been studied for decades, its regulation mechanisms still remain unclear.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In the current work, growth rate dependent acetate overflow metabolism of <jats:italic>E. coli<\/jats:italic> was continuously monitored using advanced continuous cultivation methods (A-stat and D-stat). The first step in acetate overflow switch (at \u03bc = 0.27 \u00b1 0.02 h<jats:sup>-1<\/jats:sup>) is the repression of acetyl-CoA synthethase (Acs) activity triggered by carbon catabolite repression resulting in decreased assimilation of acetate produced by phosphotransacetylase (Pta), and disruption of the PTA-ACS node. This was indicated by acetate synthesis pathways PTA-ACKA and POXB component expression down-regulation before the overflow switch at \u03bc = 0.27 \u00b1 0.02 h<jats:sup>-1<\/jats:sup> with concurrent 5-fold stronger repression of acetate-consuming Acs. This in turn suggests insufficient Acs activity for consuming all the acetate produced by Pta, leading to disruption of the acetate cycling process in PTA-ACS node where constant acetyl phosphate or acetate regeneration is essential for <jats:italic>E. coli<\/jats:italic> chemotaxis, proteolysis, pathogenesis etc. regulation. In addition, two-substrate A-stat and D-stat experiments showed that acetate consumption capability of <jats:italic>E. coli<\/jats:italic> decreased drastically, just as Acs expression, before the start of overflow metabolism. The second step in overflow switch is the sharp decline in cAMP production at \u03bc = 0.45 h<jats:sup>-1<\/jats:sup> leading to total Acs inhibition and fast accumulation of acetate.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusion<\/jats:title>\n            <jats:p>This study is an example of how a systems biology approach allowed to propose a new regulation mechanism for overflow metabolism in <jats:italic>E. coli<\/jats:italic> shown by proteomic, transcriptomic and metabolomic levels coupled to two-phase acetate accumulation: acetate overflow metabolism in <jats:italic>E. coli<\/jats:italic> is triggered by Acs down-regulation resulting in decreased assimilation of acetic acid produced by Pta, and disruption of the PTA-ACS node.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-4-166","type":"journal-article","created":{"date-parts":[[2010,12,1]],"date-time":"2010-12-01T19:15:56Z","timestamp":1291230956000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":208,"title":["Systems biology approach reveals that overflow metabolism of acetate in Escherichia coli is triggered by carbon catabolite repression of acetyl-CoA synthetase"],"prefix":"10.1186","volume":"4","author":[{"given":"Kaspar","family":"Valgepea","sequence":"first","affiliation":[]},{"given":"Kaarel","family":"Adamberg","sequence":"additional","affiliation":[]},{"given":"Ranno","family":"Nahku","sequence":"additional","affiliation":[]},{"given":"Petri-Jaan","family":"Lahtvee","sequence":"additional","affiliation":[]},{"given":"Liisa","family":"Arike","sequence":"additional","affiliation":[]},{"given":"Raivo","family":"Vilu","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2010,12,1]]},"reference":[{"key":"577_CR1","doi-asserted-by":"publisher","first-page":"530","DOI":"10.1016\/j.tibtech.2006.09.001","volume":"24","author":"MA Eiteman","year":"2006","unstructured":"Eiteman MA, Altman E: Overcoming acetate in Escherichia coli recombinant protein fermentations. 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