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Evidence of isoprenoid precursor toxicity in Bacillus subtilis
Tami L Sivy1, Ray Fall, Todd N Rosenstiel
1Department of Chemistry, Saginaw Valley State University, University Center, MI 48710, USA. tsivy@svsu.edu
Abstract:
The mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways for isoprenoid biosynthesis both culminate in the production of the two-five carbon prenyl diphosphates: dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP). These are the building blocks for higher isoprenoids, including many that have industrial and pharmaceutical applications. With growing interest in producing commercial isoprenoids through microbial engineering, reports have appeared of toxicity associated with the accumulation of prenyl diphosphates in Escherichia coli expressing a heterologous MVA pathway. Here we explored whether similar prenyl diphosphate toxicity, related to MEP pathway flux, could also be observed in the bacterium Bacillus subtilis. After genetic and metabolic manipulations of the endogenous MEP pathway in B. subtilis, measurements of cell growth, MEP pathway flux, and DMAPP contents suggested cytotoxicity related to prenyl diphosphate accumulation. These results have implications as to understanding the factors impacting isoprenoid biosynthesis in microbial systems.
Insights
Investigating isoprenoid biosynthesis in Bacillus subtilis revealed that accumulating prenyl diphosphates, key building blocks for valuable compounds, can cause cell toxicity. This finding is crucial for optimizing microbial engineering for industrial applications.
Area of Science:
- Biochemistry
- Microbiology
- Metabolic Engineering
Background:
- Isoprenoids are vital compounds with industrial and pharmaceutical applications.
- The mevalonic acid (MVA) and methylerythritol phosphate (MEP) pathways produce essential prenyl diphosphates (DMAPP and IPP).
- Previous studies in E. coli indicated toxicity from prenyl diphosphate accumulation via the MVA pathway.
Purpose of the Study:
- To investigate potential prenyl diphosphate toxicity related to MEP pathway flux in Bacillus subtilis.
- To assess the impact of MEP pathway manipulation on cell growth and DMAPP accumulation in B. subtilis.
Main Methods:
- Genetic and metabolic modifications of the endogenous MEP pathway in B. subtilis.
- Measurement of cell growth rates.
- Quantification of MEP pathway flux.
- Analysis of intracellular DMAPP content.
Main Results:
- Altered MEP pathway flux in B. subtilis led to increased DMAPP accumulation.
- Evidence suggested a correlation between prenyl diphosphate accumulation and cytotoxicity.
- Cell growth was negatively impacted under conditions of high prenyl diphosphate levels.
Conclusions:
- Prenyl diphosphate accumulation, mediated by the MEP pathway, can induce cytotoxicity in Bacillus subtilis.
- Understanding these toxicity mechanisms is critical for engineering microbes for enhanced isoprenoid production.
- These findings have significant implications for the metabolic engineering of microbial systems for industrial isoprenoid synthesis.
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