Over 40,000 compounds derived from isopentenyl pyrophosphate (IPP) have been characterized1,2. In mammals, these include: cholesterol, bile acids, steroid hormones, dolichol, coenzyme Q, and prenylated proteins. In plants, the isoprenoid pathway generates a wide variety of compounds including rubber, isoprene gas, and carotenoids. (See: http://tinyurl.com/KeggIsoPath).
The field of isoprenoid metabolism is broad-based, and includes research in areas of cell biology, pharmacology, biochemistry, immunology, microbiology, medicine, and plant physiology. Some examples:
Inhibitors of various steps in the isoprenoid pathway are used in drug therapy. Statins inhibit HMG-CoA reductase and are used to treat hypercholesterolemia. Statins appear to have pleiotropic effects beyond cholesterol lowering. To determine if the effect observed is due to inhibition of the nonsterol pathway, researchers add isoprenoid pyrophosphates (e.g., GGPP) to statin-treated cells and look for reversal. In many cases, the isoprenoid pyrophosphate has been shown to enter cells and reverse the effect, suggesting that a branch pathway is involved (e.g., protein geranylgeranylation)3,4. Confirmation can be achieved using protein prenyltransferase inhibitors.
Bisphosphonates inhibit prenyltransferase and are used to treat postmenopausal osteoporosis and tumor-induced osteolysis. As with investigating the effects of statins, isoprenoids can be added back to determine what role each compound plays in bringing about the cytotoxic effects of these drugs5,.
Fosmidomycin is an inhibitor of the nonmevalonate pathway of isoprenoid synthesis. This drug inhibits growth of Plasmodium, the microbe responsible for malaria, apparently by blocking a requirement for IPP6. Once again, adding back different isoprenoids is a strategy to determine the IPP derived metabolite necessary for survival.
Protein prenyltransferase inhibitors (FTIs, GGTIs) have been developed for use in cancer chemotherapy as well as other maladies, such as parasitic infections and progeria7,8. These enzymes use FPP and GGPP as substrates.
Screening of inhibitors that block isoprenoid pyrophosphate utilizing enzymes. The development of more effective drugs with the same targets as those mentioned above requires high throughput screening and, accordingly, an inexpensive source of high quality isoprenoid pyrophosphates.
Determination of the level of cellular isoprenoid pyrophosphate pools. To examine the effectiveness of various drugs and suss out the regulation of the key metabolic enzymes involved, several investigators have developed sensitive methods for quantifying the isoprenoid pyrophosphate levels in cells and tissue samples9,10,11.
Identification of phosphoantigens that activate γδ-T cells. These cells play an active role in adaptive immunity and perhaps tumor immunology. They are known to be activated by phosphorylated isoprenoid compounds12.
Metabolic engineering to increase the yield of terpenoid products. With the advent of genetic engineering, it is now feasible to ramp up the production of desired isoprenoids in bacteria or plants by overexpressing the enzymes involved in the rate limiting steps of isoprenoid production13.
Isoprenoids, LC, founded in 2005, is a leading producer of isoprenoid pyrophosphates and other isoprenoids. Peruse our catalog and compare our prices to other vendors. We guarantee the highest quality and lowest prices of isoprenoid compounds.
References
1 Sacchettini, James C.; Poulter, C. Dale 1997 Creating Isoprenoid Diversity. Science 277(5333) 1788-1789.
2Peñuelas J, Munné-Bosch S 2005 Isoprenoids: an evolutionary pool for photoprotection. Trends Plant Sci. Apr;10(4):166-9.
3 Song JX, Ren JY, Chen H. . 2011 Simvastatin reduces lipoprotein-associated phospholipase A2 in lipopolysaccharide-stimulated human monocyte-derived macrophages through inhibition of the mevalonate-geranylgeranyl pyrophosphate-RhoA-p38 mitogen-activated protein kinase pathway.
J Cardiovasc PharmacolFeb;57(2):213-22.
4 Ma S, Ma CC. 2011Recent development in pleiotropic effects of statins on cardiovascular disease through regulation of transforming growth factor-beta superfamily. Cytokine Growth Factor Rev. Jun;22(3):167-75.
5Räikkönen J, Mönkkönen H, Auriola S, Mönkkönen J. 2010. Mevalonate pathway intermediates downregulate zoledronic acid-induced isopentenyl pyrophosphate and ATP analog formation in human breast cancer cells. Biochem Pharmacol. Mar 1;79(5):777-83.
6Yeh E, DeRisi JL. 2011. Chemical rescue of malaria parasites lacking an apicoplast defines organelle function in blood-stage Plasmodium falciparum. PLoS Biol. Aug;9(8):e1001138
7Eastman RT, Buckner FS, Yokoyama K, Gelb MH, Van Voorhis WC. 2006. Thematic review series: lipid posttranslational modifications. Fighting parasitic disease by blocking protein farnesylation. J. Lipid Res. 47 (2): 233–40.
8 Mehta IS, Bridger JM, Kill IR. 2010. Progeria, the nucleolus and farnesyltransferase inhibitors. Biochem. Soc. Trans. 38 (Pt 1): 287–91.
9 Nürenberg, G and Volmer, DA. 2012 The analytical determination of isoprenoid intermediates from the mevalonate pathway Analytical and Bioanalytical Chemistry Volume 402, Number 2, 671-685
10Mönkkönen H, Auriola S, Lehenkari P, Kellinsalmi M, Hassinen IE, Vepsäläinen J, Mönkkönen J. 2006. A new endogenous ATP analog (ApppI) inhibits the mitochondrial adenine nucleotide translocase (ANT) and is responsible for the apoptosis induced by nitrogen-containing bisphosphonates.Br. J Pharmacol 147(4):437-45.
11Tong H, Holstein SA, Hohl RJ. 2005 Simultaneous determination of farnesyl and geranylgeranyl pyrophosphate levels in cultured cells. Anal Biochem. 336(1):51-9
12Roelofs AJ, Jauhiainen M, Mönkkönen H, Rogers MJ, Mönkkönen J, Thompson K. 2009. Peripheral blood monocytes are responsible for δγ T cell activation induced by zoledronic acid through accumulation of IPP/DMAPP. Br J Haematol. Jan;144(2):245-50.
13Peralta-Yahya PP, Zhang F, del Cardayre SB, Keasling JD. . 2012
Microbial engineering for the production of advanced biofuels. Nature 16;488(7411):320-8