Abstract
Metabolic Flux Analysis is now viewed as essential to elucidate the metabolic pattern of cells and to design appropriate genetic engineering strategies to improve strain performance and production processes. Here, we investigated carbon flux distribution in two Streptomyces coelicolor A3 (2) strains: the wild type M145 and its derivative mutant M1146, in which gene clusters encoding the four main antibiotic biosynthetic pathways were deleted. Metabolic Flux Analysis and 13C-labeling allowed us to reconstruct a flux map under steady-state conditions for both strains. The mutant strain M1146 showed a higher growth rate, a higher flux through the pentose phosphate pathway and a higher flux through the anaplerotic phosphoenolpyruvate carboxylase. In that strain, glucose uptake and the flux through the Krebs cycle were lower than in M145. The enhanced flux through the pentose phosphate pathway in M1146 is thought to generate NADPH enough to face higher needs for biomass biosynthesis and other processes. In both strains, the production of NADPH was higher than NADPH needs, suggesting a key role for nicotinamide nucleotide transhydrogenase for redox homeostasis. ATP production is also likely to exceed metabolic ATP needs, indicating that ATP consumption for maintenance is substantial.Our results further suggest a possible competition between actinorhodin and triacylglycerol biosynthetic pathways for their common precursor, acetyl-CoA. These findings may be instrumental in developing new strategies exploiting S. coelicolor as a platform for the production of bio-based products of industrial interest.
Highlights
Since the late 1960s, considerable effort has been devoted to discover new antibiotics
The soil-inhabiting, Gram-positive bacteria, belonging to the genus Streptomyces, are significant sources of new bio-active molecules [2]. While these bacteria produce up to 70% of antibiotics currently used in medical prescriptions as well as many valuable compounds, recent publications of the genome sequence from several Streptomyces species [3,4,5] highlighted that their potential for the production of new secondary metabolites remains enormous
Analysis and 13C Metabolic Flux Analysis yielded an accurate description of carbon fluxes in S. coelicolor under steady-state conditions
Summary
Since the late 1960s, considerable effort has been devoted to discover new antibiotics. Discovering novel antibiotics is seen as critical for public health and medical research programs. In this regard, the soil-inhabiting, Gram-positive bacteria, belonging to the genus Streptomyces, are significant sources of new bio-active molecules [2]. The soil-inhabiting, Gram-positive bacteria, belonging to the genus Streptomyces, are significant sources of new bio-active molecules [2] While these bacteria produce up to 70% of antibiotics currently used in medical prescriptions as well as many valuable compounds (such as immune-suppressors or anticarcinogenic agents), recent publications of the genome sequence from several Streptomyces species [3,4,5] highlighted that their potential for the production of new secondary metabolites remains enormous. Genome mining revealed that for a given Streptomyces species, the genome comprises 20 to 40 gene clusters presumably involved in the production of many secondary metabolites, while three to five only are currently produced under ordinary laboratory culture conditions
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