title: A modular modulation method for achieving increases in metabolite production.
abstract: Increasing the production of overproducing strains represents a great challenge. Here, we develop a modular modulation method to determine the key steps for genetic manipulation to increase metabolite production. The method consists of three steps: (i) modularization of the metabolic network into two modules connected by linking metabolites, (ii) change in the activity of the modules using auxiliary rates producing or consuming the linking metabolites in appropriate proportions and (iii) determination of the key modules and steps to increase production. The mathematical formulation of the method in matrix form shows that it may be applied to metabolic networks of any structure and size, with reactions showing any kind of rate laws. The results are valid for any type of conservation relationships in the metabolite concentrations or interactions between modules. The activity of the module may, in principle, be changed by any large factor. The method may be applied recursively or combined with other methods devised to perform fine searches in smaller regions. In practice, it is implemented by integrating to the producer strain heterologous reactions or synthetic pathways producing or consuming the linking metabolites. The new procedure may contribute to develop metabolic engineering into a more systematic practice.
authors: Systems Biology Laboratory, Faculty of Sciences, Universidad de la República, Iguá 4225, Montevideo, 11400, Uruguay.
authors: Luis
authors: L
authors: Acerenza
authors: School of Engineering, Universidad de la República, Julio Herrera y Reissig 565, Montevideo, 11300, Uruguay.
authors: Pablo
authors: P
authors: Monzon
authors: Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, M13 9PT, UK.
authors: Fernando
authors: F
authors: Ortega
mesh_terms: D060847:Metabolic Engineering / Q000379:methods*; D053858:Metabolic Networks and Pathways; D008962:Models, Theoretical
keywords: metabolic engineering; metabolite production; modularization; synthetic biology; systems biology