FAIRDOMHubModelsThomas Millathttps://fairdomhub.org/models/100?version=1Matlab packageUniversity of RostockFAIRDOMHubClostridium acetobutylicum is able to switch from acidogenic growth to solventogenic growth. We used phosphate-limited continuous cultures that established acidogenic growth at pH 5.8 and solventogenic growth at pH 4.5. These cultures allowed a detailed transcriptomic study of the switch from acidogenesis to solventogenesis that is not superimposed by sporulation and other growth phase-dependent parameters. These experiments led to new insights into the physiological role of several genes involved in solvent formation. The adc gene for acetone decarboxylase is upregulated well before the rest of the sol locus during the switch, and pyruvate decarboxylase is induced exclusively for the period of this switch. The aldehyde-alcohol dehydrogenase gene adhE1 located in the sol operon is regulated antagonistically to the paralog adhE2 that is expressed during acidogenic conditions. A similar antagonistic pattern can be seen with the two paralogs of thiolase genes, thlA and thlB. Interestingly, the genes coding for the putative cellulosome in C. acetobutylicum are exclusively transcribed throughout solventogenic growth. The genes for stress response are only induced during the shift but not in the course of solventogenesis when butanol is present in the culture. Finally, the data clearly indicate that solventogenesis is independent from sporulation.In response to changing extracellular pH levels, phosphate-limited continuous cultures of Clostridium acetobutylicum reversibly switches its metabolism from the dominant formation of acids to the prevalent production of solvents. Previous experimental and theoretical studies have revealed that this pH-induced metabolic switch involves a rearrangement of the intracellular transcriptomic, proteomic and metabolomic composition of the clostridial cells. However, the influence of the population dynamics on the observations reported has so far been neglected. Here, we present a method for linking the pH shift, clostridial growth and the acetone-butanol-ethanol fermentation metabolic network systematically into a model which combines the dynamics of the external pH and optical density with a metabolic model. Furthermore, the recently found antagonistic expression pattern of the aldehyde/alcohol dehydrogenases AdhE1/2 and pH-dependent enzyme activities have been included into this combined model. Our model predictions reveal that the pH-induced metabolic shift under these experimental conditions is governed by a phenotypic switch of predominantly acidogenic subpopulation towards a predominantly solventogenic subpopulation. This model-driven explanation of the pH-induced shift from acidogenesis to solventogenesis by population dynamics casts an entirely new light on the clostridial response to changing pH levels. Moreover, the results presented here underline that pH-dependent growth and pH-dependent specific enzymatic activity play a crucial role in this adaptation. In particular, the behaviour of AdhE1 and AdhE2 seems to be the key factor for the product formation of the two phenotypes, their pH-dependent growth, and thus, the pH-induced metabolic switch in C. acetobutylicum.A shift in the dominant phenotype governs the pH-induced metabolic switch of Clostridium acetobutylicumin phosphate-limited continuous cultures.Genome-wide gene expression analysis of the switch between acidogenesis and solventogenesis in continuous cultures of Clostridium acetobutylicum.Grimmler Christina C, Janssen Holger H, Krausse Desireé D, Fischer Ralf-Jörg RJ, Bahl Hubert H, Dürre Peter P, Liebl Wolfgang W, Ehrenreich Armin AMillat Thomas T, Janssen Holger H, Thorn Graeme J GJ, King John R JR, Bahl Hubert H, Fischer Ralf-Jörg RJ, Wolkenhauer Olaf OPh Negative, Inorganic Phosphate, Phosphates, [PO4](3-), tetraoxophosphate(3-), tetraoxophosphate(V), Metabolic Process, Orthophosphate, Metabolic, PHOSPHATE ION, Metabolized, tetraoxidophosphate(3-), PO4(3-), Inorganic Phosphates, Inducing, Ph-, Phosphate, Pi, Physical Shift, metabolic, Inducible, Shift, Induction, phosphate, phosphate ions, Metabolism, Displacement, Cellular, Switch, Switch Device., phosphates, Induce, cellular metabolism, Philadelphia Chromosome Negative, metabolism, Switch/Relay, Inorganic, InducedInorganic Phosphate, Phosphates, [PO4](3-), Phenotypes, tetraoxophosphate(3-), tetraoxophosphate(V), Anaerobacter, Orthophosphate, Inorganic., phosphate, phosphate ions, PHOSPHATE ION, tetraoxidophosphate(3-), PO4(3-), Inorganic Phosphates, Phosphate, phosphates, Pi, Anaerobacter Duda et al. 1996, InorganicPh Negative, Inorganic Phosphate, Phosphates, [PO4](3-), tetraoxophosphate(3-), tetraoxophosphate(V), Metabolic Process, Orthophosphate, Metabolic, PHOSPHATE ION, Metabolized, tetraoxidophosphate(3-), PO4(3-), Inorganic Phosphates, Inducing, Ph-, Phosphate, Pi, Physical Shift, metabolic, Inducible, Shift, Induction, phosphate, phosphate ions, Metabolism, Displacement, Cellular, Switch, Switch Device., phosphates, Induce, cellular metabolism, Philadelphia Chromosome Negative, metabolism, Switch/Relay, Inorganic, InducedTAPETUM 1, BG:DS00941.5, Materials, postnatal development, Carboxy-Lyase, nofE, growth and development, cDNA 1, Pi, HIV Associated Cognitive Motor Complex, Solvent, HuADC, 2-Propanone, Background, acquired immune deficiency syndrome dementia complex, ascospore biosynthesis, Acquired-Immune Deficiency Syndrome Dementia Complex, Poly(methyl methacrylate), Cultural, alpha Carboxylase, Alcohol:NAD+ oxidoreductase, PC79, HIV 1 Cognitive and Motor Complex, Alcohol-NAD+, methyl ketone, multicellular organismal biosynthetic process, AIDS with dementia (disorder), Implast, odc1l, tetraoxophosphate(V), single-organism biosynthetic process, ethnicity, Oxidoreductase, Orthophosphate, Methacrylate, PHOSPHATE ION, Rests, tetraoxidophosphate(3-), Decarboxylases, Acquired Immune Deficiency Syndrome, spore formation, AIDS Dementia, ASD, HIV-Associated Cognitive Motor Complex, Carboxy Lyase, Phosphate, sporulation, HIV 1 Associated Cognitive Motor Complex, sporulation., Decarboxylase, Butylhydroxides, 2-Oxo Acid, Alcohol-NAD+ Oxidoreductase, AIDS RELAT DEMENTIA COMPLEX, Propanon, HIV ASSOC COGNITIVE MOTOR COMPLEX, Palacos R, PMMA, Simplex Opaque, w5000, Inorganic, HIV-1-Associated Cognitive Motor Complex, ADC, AIDS - Acquired immune deficiency syndrome dementia complex, Palavit, AIDS Encephalopathies, Perspex, acquired immune deficiency syndrome-related dementia, Alcohol, dimethylketone, Pyruvic, GAD[[2]], Methyl Acrylic Plastic, Carboxylase, Alcohol Dehydrogenase (NAD+), AIDS related cognitive impairment, Aceton, Yeast Alcohol Dehydrogenase, Cultural Belief, Menstruation, Alcohol Dehydrogenase II, Cultural Background, Plexiglas, Syndiostatic Polymethyl Methacrylate, Pyroacetic ether, Cultures, AIDS, XBR, Operons, Acquired immune deficiency syndrome dementia complex, Genetic Materials, Ammonium Salt, Polymethylmethacrylate, HIV-associated dementia, Genetic Material, HIV Dementias, Dementia, Phosphates, odc1-b, Yeast, 2 Oxo Acid Carboxy Lyase, Cultural Beliefs, growth pattern, Polymethyl Methacrylate, 4.1.1.11, non-developmental growth, PO4(3-), azi2, Lucite, DGad2, Dementias, Encephalopathy, INSDC_feature:gene, DmGad2, beta-Ketopropane, CMW Bone Cement, DEMENTIA COMPLEX ACQUIRED IMMUNE DEFIC SYNDROME, 4.1.1.29, phosphate, Pyruvate, Gad2, phosphate ions, Material, 1110027M19Rik, Aldehyde, Butyl, Cistron, Isostatic Polymethyl Methacrylate, HIV Encephalopathy, alpha-Carboxylase, odc2, Dementia associated with acquired immunodeficiency syndrome, Gruppe, Syndiostatic Polymethyl, AA407358, AIDS-related Dementia, ALCOHOL DEHYDROGENASE, tetraoxophosphate(3-), Encephalopathies, Butyl Alcohols, Dehydrogenase, Acid Carboxy-Lyase, Clostridium acetobutyricum, Gene, solventogenesis, Coding, alpha-Ketoacid Carboxylase, propanone, Syndiostatic, TAPETUM1, AIDS related Dementia Complex, HIV Encephalopathies, Clostridium acetonobutylicum, thiolase, Polymethylmetacrylate, dimethylcetone, NRSF, Dementia associated with AIDS, Butanol, Medical, HuCSADC, Polymethyl, Dementia Complex, Backgrounds, HIV encephalitis, study, Genetic, Clinical, CG1391, Medical Coding, Acrylic Bone Cement, Complex, Granulobacter pectinovorum, Inorganic Phosphates, Cysteine sulfinic acid decarboxylase, Cultural Relativisms, Superacryl, alpha Ketoacid Carboxylase, Alcohol Dehydrogenase I, Isostatic, acidogenesis, Cellulosome, TA1, Surgical Simplex P, Custom, grupos, Customs, Sol, SOL, CG7811, HIV, Azeton, culture, Dimethyl ketone, Yeast Alcohol, Alcohol NAD+ Oxidoreductase, [PO4](3-), Dimethylketon, grupo, Alcohol Dehydrogenase, AIDS-related, Acron, 2610008J04Rik, Kallocryl K, 2-Oxo Acid Carboxy-Lyase, ADC - Acquired immune deficiency syndrome dementia complex, TelN, alpha-Ketoacid, Hydroxybutanes, Cultural Backgrounds, DEMENTIA COMPLEX AIDS RELAT, Cistrons, HIV-1 Cognitive and Motor Complex, group, scaffoldin complex, Belief, development, Surgical Simplex Bone Cement, AIDS Encephalopathy, Carboxy Lyases, Period, AIDS Dementia Complex, AIDS-related Dementia Complex, Pyruvic Decarboxylase, Glutamate decarboxylase-like protein 1, 2-Oxo, Inorganic Phosphate, DmelCG7811, CSADC, Alcohols, postnatal growth, Rest, DmSol, odc-p, Plexiglass, DmelCG1391, CalpD, Aspartate 1-decarboxylase, anon-34Db, AIDS related, HIV Dementia, ResT, Relativisms, HIV associated cognitive and motor complex, phosphates, Relativism, Cultural Relativism, growth, groupe, Acquired immune deficiency syndrome-related dementiafalseModel of the pH-induced metabolic shift in phosphate-limited continuous cultures of C. acetobutylicum assuming a phenotypic switchModel of the pH-induced metabolic shift in phosphate-limited continuous cultures of C. acetobutylicum assuming a phenotypic switch2013-01-062013-01-062013-01-062013-01-061002121268823640360