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This article is part of the supplement: BioSysBio 2007: Systems Biology, Bioinformatics, Synthetic Biology

Open Access Oral presentation

Metabolic flux analysis to study the production of a non-ribosomal lipopeptide, CDA, by Streptomyces coelicolor

Raul Munoz-Hernandez*, Ana Katerine de Carvalho Lima Lobato, Hong Bum Kim and Ferda Mavituna

Author Affiliations

The School of Chemical Engineering and Analytical Science, The University of Manchester, Sackville St, PO Box 88, Manchester, M60 1QD, UK

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BMC Systems Biology 2007, 1(Suppl 1):S3  doi:10.1186/1752-0509-1-S1-S3


The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1752-0509/1/S1/S3


Published:8 May 2007

© 2007 Munoz-Hernandez et al; licensee BioMed Central Ltd.

Background

The Calcium Dependent Antibiotic (CDA) from S. coelicolor is a non-ribosomally synthesised lipopeptide which consists of 11 amino acids to which a lipid part has been attached [1]. Although the mode of action for CDA is not yet known, antibiotics with similar structure like daptomycin or friulimicin inhibit bacterial cell wall synthesis. CDA-related drugs therefore, may become very important in treating infections from severe antibiotic resistant pathogens, such as methicillin-resistant Staphylococcus aureus strains (MRSA) and vancomycin-resistant enterococci (VRE). CDA contains several nonproteinogenic amino acids, crucially L-4-hydroxyphenylglycine (HPG). This amino acid is also present in the backbone of various important therapeutics such as; peptides (complestatin and nocardicin), glycopeptides, (vancomycin and teicoplanin), further lipopeptides (arylomycin), and the lipoglycodepsipeptide antibiotic ramoplanin.

Model construction

In this work, a metabolic model for S. coelicolor was constructed using the metabolic flux analysis approach [2]. The metabolic model involved around 250 reactions of the primary and secondary metabolism leading to CDA formation. We used the model for in silico experimentation and prediction of the internal metabolite fluxes under different conditions during S. coelicolor fermentation, either for the maximisation of growth or CDA production using linear programming in GAMS software.

Results

The comparison of internal metabolite fluxes between the maximisation of growth and CDA production revealed important changes in fluxes related to NADPH (Pentose Phosphate pathway), CDA amino acid precursors (serine, glycine, HPG and tryptophan) and NADH. We are now using this model in predictive mode in order to develop strategies to increase CDA productivity; such as, media formulation, precursor addition and identification of genetic engineering targets.

Conclusion

Computational metabolic flux analysis can be used in order to study the interrelationship between the primary metabolism and biosynthetic pathways for CDA, as well as for the in silico experimentation for the identification of genetic engineering targets for increased production. It can also be used to investigate any precursor effects for precursor-directed biosynthesis combined with genetic engineering.

Acknowledgements

Consejo Nacional de Ciencia y Tecnología (CONACYT), México.

References

  1. Hojati Z, Milne C, Harvey B, Gordon L, Borg M, Flett F, Wilkinson B, Sidebottom PJ, Rudd BAM, Hayes MA, Smith CP, Micklefield J: Structure, biosynthetic origin, and engineered biosynthesis of calcium-dependent antibiotics from Streptomyces coelicolor.

    Chem Biol 2002, 9(11):1175-1187. PubMed Abstract | Publisher Full Text OpenURL

  2. Kim HB, Smith CP, Micklefield J, Mavituna F: Metabolic flux analysis for calcium dependent antibiotic (CDA) production in Streptomyces coelicolor.

    Metab Eng 2004, 6:313-325. PubMed Abstract | Publisher Full Text OpenURL