title: Flux balance analysis in the production of clavulanic acid by Streptomyces clavuligerus.
abstract: In this work, in silico flux balance analysis is used for predicting the metabolic behavior of Streptomyces clavuligerus during clavulanic acid production. To choose the best objective function for use in the analysis, three different optimization problems are evaluated inside the flux balance analysis formulation: (i) maximization of the specific growth rate, (ii) maximization of the ATP yield, and (iii) maximization of clavulanic acid production. Maximization of ATP yield showed the best predictions for the cellular behavior. Therefore, flux balance analysis using ATP as objective function was used for analyzing different scenarios of nutrient limitations toward establishing the effect of limiting the carbon, nitrogen, phosphorous, and oxygen sources on the growth and clavulanic acid production rates. Obtained results showed that ammonia and phosphate limitations are the ones most strongly affecting clavulanic acid biosynthesis. Furthermore, it was possible to identify the ornithine flux from the urea cycle and the α-ketoglutarate flux from the TCA cycle as the most determinant internal fluxes for promoting clavulanic acid production.
authors.affiliation: Grupo de Investigación Nutrición Y Tecnología de Alimentos, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Grupo de Investigación Bioprocesos, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Quintero
authors.affiliation: Grupo de Investigación SIDCOP, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Ochoa
mesh_terms: D002244:Carbon / Q000378:metabolism; D002952:Citric Acid Cycle; D019818:Clavulanic Acid / Q000096:biosynthesis*; D007656:Ketoglutaric Acids / Q000378:metabolism; D064688:Metabolic Flux Analysis / Q000379:methods*; D009584:Nitrogen / Q000378:metabolism; D013302:Streptomyces / Q000378:metabolism*
chemical_list: D007656:Ketoglutaric Acids; D019818:Clavulanic Acid; D002244:Carbon; D009584:Nitrogen
keywords: Streptomyces clavuligerus; clavulanic acid; flux balance analysis; nutrient limitation; β-lactamase inhibitors