Metabolic flux analysis for directing metabolism of Streptomyces olindensis from growth to anti-tumor drug (cosmomycin) production

Abstract

Background Cosmomycin, an aromatic polyketide antibiotic complex produced by Streptomyces olindensis, belongs to anthracycline family of chemotherapy drugs. It is a powerful antitumor drug similar to doxorubicin and daunorubicin. The structure of cosmomycin consists of one tetracycline aglycon (β-rhodomycinone) and six deoxysugars (two dTDPL-2-deoxifucose, two dTDP-L-rodosamine and two dTDPL-rodinose). The tetracycline aglycon, a polyketide structure, is obtained by condensation of one propionyl-CoA with nine acetate molecules derived from malonyl-CoA by the action of enzymes known as minimal Polyketide Synthetases (minimal PKS). Model construction The in silico metabolism was reconstructed involving more than 240 stoichiometrically balanced metabolic reactions in matrix formalism using the information from the literature and databases (top-down and bottom-up). Then, computational metabolic flux balancing method was used in order to obtain fluxes of all the metabolic reactions with linear programming and optimisation in GAMS environment (General Algebraic Modeling System). The objective function of optimisation was either the maximisation of the specific growth rate or the maximisation of the specific cosmomycin production rate. The experimental specific glucose uptake and growth rates were used as the model constraints, as appropriate. The solution of the metabolic model gave the specific growth and/or product formation rates as well as the specific rates of all 242 metabolic reactions.