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Background  Protoilludene is a valuable sesquiterpene and serves as a precursor for several medicinal compounds and antimicrobial chemicals. It can be synthesized by heterologous expression of protoilludene synthase in  Escherichia  coli  with overexpression of mevalonate (MVA) or methylerythritol-phosphate (MEP) pathway, and farnesyl diphosphate (FPP) synthase. Here, we present  E. coli  as a cell factory for protoilludene production.    Results  Protoilludene was successfully produced in  E. coli  by overexpression of a hybrid exogenous MVA pathway, endogenous FPP synthase (IspA), and protoilludene synthase (OMP7) of  Omphalotus  olearius . For improving protoilludene production, the MVA pathway was engineered to increase synthesis of building blocks isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP) by sequential order permutation of the lower MVA portion (MvL), the alteration of promoters and copy numbers for the upper MVA portion (MvU), and the coordination of both portions, resulting in an efficient entire MVA pathway. To reduce the accumulation of mevalonate observed in the culture broth due to lower efficiency of the MvL than the MvU, the MvL was further engineered by homolog substitution with the corresponding genes from  Staphylococcus  aureus . Finally, the highest protoilludene production of 1199 mg/L was obtained from recombinant  E .  coli  harboring the optimized hybrid MVA pathway in a test tube culture.    Conclusions  This is the first report of microbial synthesis of protoilludene by using an engineered  E. coli  strain. The protoilludene production was increased by approx. Thousandfold from an initial titer of 1.14 mg/L. The strategies of both the sequential order permutation and homolog substitution could provide a new perspective of engineering MVA pathway, and be applied to optimization of other metabolic pathways.    Electronic supplementary material  The online version of this article (doi:10.1186/s12934-016-0409-7) contains supplementary material, which is available to authorized users.

Combinatorial engineering of hybrid mevalonate pathways in Escherichia coli for protoilludene production