Isoprenoids

Isoprenoids are among some of the oldest known biomolecules. This class of chemicals is of significant interest due to the breadth of applications across various industries including medical, agricultural, nutrition, cosmetics, and others. Biochemically, the molecules serve as quinones in the electron transport chain, as membrane components, as photosynthetic pigments, as hormones, and as plant defense compounds. Naturally occurring isoprenoids are ubiquitously derived from isopentenyl diphosphate (IPP) or dimethylallyl diphosphate (DMAPP). Biologically, these precursors are produced from one of two pathways: the mevalonate (MVA) pathway or the nonmevalonate (MEP or DXP) pathway. Once produced, IPP and DMAPP are condensed to generate larger isoprenoid precursors such as geranyl diphosphate, farnesyl diphosphate, and geranylgeranyl diphosphate which can then be further functionalized.

Synthetic isoprenoids are useful tools to investigate the specificity and mechanism of prenylation in cells. Protein modification with isoprenoids, prenylation, has been an active area of study since the 1990s when its connection to cancer was identified. Protein farnesyltransferase and geranylgeranyltransferase catalyze the transfer of farnesyl and geranylgeranyl from the diphosphate to a cysteine residue within the C-terminal amino acid sequence of the protein. After prenylation, proteins can then move to the endoplasmic reticulum for further processing or post-translational modifications. Protein prenylation is essential for functional biochemical signaling stimulating continued interest in the process of post-translational modifications of proteins. For this, synthetic isoprenoids and isoprenoid analogues have proven to be invaluable tools.

References:

Chatzivasileiou, A. O., Ward, V., Edgar, S. M., & Stephanopoulos, G. (2019). Two-step pathway for isoprenoid synthesis. Proceedings of the National Academy of Sciences of the United States of America, 116(2), 506–511.

Lange, B. M., Rujan, T., Martin, W., & Croteau, R. (2000). Isoprenoid biosynthesis: the evolution of two ancient and distinct pathways across genomes. Proceedings of the National Academy of Sciences of the United States of America, 97(24), 13172–13177.

Wang, Y. C., & Distefano, M. D. (2016). Synthetic isoprenoid analogues for the study of prenylated proteins: Fluorescent imaging and proteomic applications. Bioorganic chemistry, 64, 59–65.