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The analytical determination of isoprenoid intermediates from the mevalonate pathway

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Abstract

In this article, assays on the analytical determination of farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), two important isoprenoid intermediates at biochemically relevant branching points in the mevalonate pathway, are summarized and reviewed. There is considerable recent interest in the measurement of these two isoprenoids because of their direct involvement in several diseases, for example, statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase but equally affect other metabolite biosyntheses. The isoprenoids FPP and GGPP are key intermediates due to their role as CaaX-specific substrates for posttranslational modification of proteins (protein prenylation). Disease pathologies and therapeutic efficacy of different treatments (e.g., cholesterol-lowering drugs) may lead to a reduction in isoprenoid levels and an accompanying reduction in prenylation of specific proteins. To understand the exact biochemical role of the isoprenoids FPP and GGPP, we need to know their levels. Several recent studies have shown exact levels of FPP and GGP in plasma and relevant tissues and their modulation following treatment. Furthermore, by directly measuring the extent of protein prenylation and identifying target proteins, further insight into the exact biochemical nature of the pathology and regulatory mechanisms will be possible. This short review aims to highlight the relevant literature on the analytical determination of the free isoprenoids FPP and GGPP in biological tissue as well as techniques for directly measuring prenylated proteins.

Isoprenoid derivatives for labeling peptides and proteins via prenylation reactions. (1) Dye-containing derivatives; (2) derivatives for orthogonal labeling after prenylation (a); (b) via Staudinger reaction with azide isoprenoids or (c) via Click chemistry ([3+2] cycloaddition) with azide or alkyne isoprenoids (circles, dye and biotinyl group)

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Acknowledgment

DAV acknowledges research support by the Alfried Krupp von Bohlen und Halbach-Stiftung.

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Correspondence to Dietrich A. Volmer.

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Nürenberg, G., Volmer, D.A. The analytical determination of isoprenoid intermediates from the mevalonate pathway. Anal Bioanal Chem 402, 671–685 (2012). https://doi.org/10.1007/s00216-011-5262-2

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