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Revealing the hidden secrets of the MEP pathway to engineer new bio-resources for humanity

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Hidden secrets of the MEP pathway show a new path to isoprenoid production

Research under the BioHelp project has helped advance scientific knowledge of MEP pathway regulation, as well as identify promising targets for new drugs. Potential applications for the project’ outcomes range from cancer treatment to biofuel development and crop biofortification.

Health

Isoprenoids can be found almost everywhere in nature and industrial products – they are an essential component of a wide range of products including pharmaceuticals, fragrances and biofuels. However widely occurring, isoprenoids are very difficult to extract from plants, their main natural source. Only very expensive and environmentally-damaging chemical synthesis can result in exploitable isoprenoids. Thanks to the EU-funded BioHelp project, that may be about to change. BioHelp which started in 2014, has been building upon the discovery of the MEP pathway – a complex metabolic pathway responsible for the production of the universal building blocks used to produce all isoprenoids – in the early 90s. The project aimed to unveil the mechanisms controlling each step of this pathway in bacteria, with a view to enabling the creation of biorefineries producing isoprenoids at industrial scale. “Before BioHelp, most research was based on in vitro studies or conducted in isolation from the context of the entire pathway and/or the whole cell. This is the first time the MEP pathway has been studied from a broader perspective to obtain pathway-wide in vivo kinetic parameters,” says Dr Jordi Perez-Gil. Two teams have been involved in the project: Spain’s Center for Research in Agricultural Genomics (CRAG) and Australia’s University of Queensland. The project was coordinated by Dr Manuel Rodriguez-Concepcion (CRAG). The teams combined the production of multiple bacterial strains, including modified versions of the MEP pathway, with advanced analytical techniques. The point was to characterize them and use this valuable data to set up an innovative, adaptive, in silico modelling approach. “Most results have yet to be published, but we have notably been able to generate a model for the first five steps of the MEP pathway. We identified new specific regulatory mechanisms controlling this pathway, characterised new and relevant properties of one of the pathway enzymes, and provided a much broader picture of its overall regulation. We also set up the foundations of a synthetic system to export specific isoprenoids (carotenoids) from bacterial biofactories. The latter opens new lines of research on the fundamental aspects of carotenoid transport and accumulation in plants,” Dr Perez-Gil explains. On the antibiotic front, the project teams have focused on a new enzyme of the MEP pathway that is only present in a few pathogenic microorganisms. This research opens a new path to antibiotic development which is much needed in the context of increasing antibiotic resistance. “Using enzyme-specific antibiotics might become a more common approach in the coming years. Thanks to our discovery, we could create new antibiotics for the treatment of highly prevalent diseases in third world countries. We could establish a new generation of antibiotics which could the target specific pathogens that harbour the newly discovered enzyme while preventing damage to the beneficial microbiota. We could even treat of Brucella abortus – a pathogen affecting cattle causing great economic damage in the European Union,” Dr Perez-Gil enthuses. In a foreseeable future, Dr Perez-Gil is hopeful that the project will help implement a new industrial biotechnology-based paradigm, and he plans on continuing his work based on BioHelp outcomes and other recent developments in the field.

Keywords

BioHelp, isoprenoids, MEP pathway, antibiotic resistance, antibiotics, plants

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