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Understanding the MEP Pathway for the Production of Terpenoids

Facing an increasing demand of sustainable energy and chemicals, new strategies have to be explored to synthesize these in low-cost and environmental friendly processes. Isoprenoids are a promising source for a broad spectrum of valuable molecules, including bulk chemicals, fuels, and pharmaceuticals. Isoprenoids are one of the largest as well as most diverse class of chemical molecules synthesized by the natural world. All isoprenoids are derived from two common precursors, isopentenyl phosphate and dimethylallyl phosphate, which are synthesized via two distinct pathways. The long known mevalonate (MVA) pathway uses Acetyl-CoA as substrate, while the recently discovered methylerythritol 4-phosphate (MEP) pathway uses glycerinaldehyd-3-phosphat and pyruvate.

The economical production of many terpenoids is hindered by either the inefficiency of the terpene synthase used or the limited supply of precursor from the upstream pathway. Most economic applications use the MVA pathway, because it is well understood, despite its theoretical lower yield than the MEP pathway. This is due to our lack of knowledge about the MEP pathway and its regulation.

The aim of this study is to elucidate the regulation and the kinetics of the MEP pathway. We investigate the pathway on several levels, in order to identify limiting factors in the MEP pathway, Through the use of recombineering we introduced variation in the expression of the enzymes involved in the MEP pathway. Different strains with different expression characteristics were investigated on their behavior through targeted proteomics and metabolomics as well as non-stationary 13C metabolic flux analysis. These methods revealed intrinsic regulation in the pathway and the data is further used to establish an in silico kinetic model of the pathway and will allow us to engineer the pathway more efficient.