The isoprenoid pathway is one of the most essential metabolic pathways in biology as it leads to the formation of all terpenes and prenylated molecules. In mammals, the precursors to the isoprenoid pathway, isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) are products of the mevalonic acid (MVA) pathway. DMAPP is a direct result of the isomerization of IPP which is catalyzed by isopentenyl pyrophosphate isomerase (IPPI). Exogenous IPP and DMAPP are not cell-permeant because of their charged pyrophosphate; however, we have recently solved this problem by synthesizing masked analogs where the β phosphate is protected with self-immolating esters. To study the individual function of IPP and DMAPP and the downstream products in the isoprenoid biosynthesis pathway, known inhibitors of IPPI have been employed in order to eliminate native production of DMAPP. These inhibitors are also not cell permeant for the same reason as with IPP/DMAPP, so the previously described masking strategy was employed to make cell permeant IPPI inhibitors. Here we show that by using these inhibitors, we can identify small molecules that descend from either IPP or DMAPP. Carbon-13 labeled analogues of IPP and DMAPP in addition to the inhibitors are exogenously introduced to replace the native compounds and simultaneously inhibit IPPI. Subsequently, liquid chromatography high-resolution mass spectrometry (LC-HRMS) was utilized to discover novel isoprenoids. Identification of small molecules that derive from only IPP or DMAPP was previously not possible and expands our understanding of the isoprenoid pathway.

<i>In-vivo</i> inhibition of isopentenyl pyrophosphate isomerase

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In-vivo inhibition of isopentenyl pyrophosphate isomerase