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Metabolic flux analysis for the in silico optimization of the production of biocompounds by Streptomyces clavuligerus


The diversity of bioactive compounds produced by Streptomyces clavuligerus, several of them of great therapeutic interest (cephalosporins, clavulanic acid, holomycin, tunicamycin), made this species an excellent model to study the interrelationships of mechanisms governing secondary metabolism. There are many studies reporting separately discovery and/or elucidation of genes, enzymes, regulatory mechanisms and production processes. However, major advances in proposing strategies to increase production of biocompounds have been hindered by lack of data on the dynamics between primary and secondary metabolism in S. clavuligerus. Methodologies of metabolic flux analysis are potential tools of Metabolic Engineering to perform such studies. In this approach to study biological systems, the use of stoichiometric calculations, data from the "omics" (genomics, metabolomics, proteomics), and in vivo data to build models allows to evaluate the distribution of operational fluxes in the organism. Simulations enable one to obtain solutions for distribution of the fluxes that allow to propose improvements in the bioprocess with the aid of Molecular Biology tools and/or Bioprocess Engineering. This project proposes a holistic study of the metabolism of S. clavuligerus via metabolic flux analysis. The comparison between the behaviors of a mutant (Hol-80), obtained in our Laboratories (Proc. FAPESP 08/03579-1), and the wild type strain (ATCC 27064) will serve to deepen the understanding of the species. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CAVALLIERI, ANDRE PASTRELO; BAPTISTA, AMANDA SALVADOR; LEITE, CARLA ANDREA; GONSALES DA COSTA ARAUJO, MARIA LUCIA. A case study in flux balance analysis: Lysine, a cephamycin C precursor, can also increase clavulanic acid production. Biochemical Engineering Journal, v. 112, p. 42-53, AUG 15 2016. Web of Science Citations: 2.
LEITE, CARLA A.; CAVALLIERI, ANDRE P.; BAPTISTA, AMANDA S.; ARAUJO, MARIA L. G. C. Dissociation of cephamycin C and clavulanic acid biosynthesis by 1,3-diaminopropane in Streptomyces clavuligerus. FEMS Microbiology Letters, v. 363, n. 1 JAN 2016. Web of Science Citations: 1.
LEITE, CARLA A.; CAVALLIERI, ANDRE P.; ARAUJO, MARIA L. G. C. Enhancing effect of lysine combined with other compounds on cephamycin C production in Streptomyces clavuligerus. BMC Microbiology, v. 13, DEC 20 2013. Web of Science Citations: 2.

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