Isopentenyl pyrophosphate (IPP) and dimethylallylpyrophosphate (DMAPP) are the five-carbon precursors to all isoprenoids in all organisms. IPP and DMAPP are however not cell permeant due to their short carbon chain and negatively charged pyrophosphate, which has hindered the study of the individual functions of these molecules, as exogenous addition is not possible. Our previous work focused on solving this problem via the synthesis and delivery of IPP and DMAPP that are masked on the β-phosphate with self-immolating esters. The cellular delivery of these analogs was not cell-specific as they are activated in the presence of general native esterases found in a variety of mammalian cells. Here, we develop a cell-specific pro-drug strategy for the incorporation of IPP and DMAPP into subcellular populations in co-cultures. We used porcine liver esterase (PLE)- and nitroreductase (NTR)- dependent protecting groups, such that only cells expressing these enzymes will release IPP and DMAPP. We show cells treated with statins, which inhibit native IPP and DMAPP production and cause cell death, are rescued by the expression of PLE or NTR with the exogenous addition of IPP and DMAPP analogs. Our results demonstrate that cell-specific delivery of IPP and DMAPP can provide an avenue to track isoprenoid metabolites that are involved in cellular communication. We anticipate this strategy could be employed for metabolic labeling of other cell impermeant metabolic precursors, which could provide a more comprehensive picture of cellular communication in mixed cell populations often found in disease.

Cell-specific delivery of isoprenoid precursors in mammalian cells

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