In all organisms, the structurally related five-carbon metabolites, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are the central precursors to all isoprenoids. The ability to chemically differentiate the metabolic fate of IPP and DMAPP in cells requires isotopically distinguishing the two structurally related precursors and creating cell-permeant analogs. For this reason, we have sought to synthesize 13C-labeled IPP and DMAPP with a known and distinct heavy isotope pattern. Here we present the synthesis of the cell-permeant IPP and DMAPP isotopologues. The synthesis of 3-13C DMAPP has been successfully completed through a 5-step route beginning with ethyl bromoacetate and [13C3] acetone. Its cell-permeant analog has been made using a cleavable esterase chain for in-vivo application. The synthesis of 4-13C IPP is currently near completion of its 8-step route starting from [1,2,3,4-13C4] ethyl acetoacetate, which will be converted into the cell-permeant analog in the same manner as the DMAPP analogs. These will soon be utilized in metabolic incorporation experiments in Mycolicibacterium smegmatis to identify novel isoprenoids biosynthesized and distinguish their metabolic origins between IPP and DMAPP.

In-vivo isotopic labeling in the mevalonic acid pathway

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