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Chemical Compound Review:

AC1NRBOB [(1S)-1-hydroxy-3,7,11- trimethyl...

Synonyms:

Brennan, L.A. et al., Mau, C.J. et al., Wu, Z. et al., Goalstone, M.L. et al., Goalstone, M.L. et al., et al.

Lee, Han, Wu, Demma, Strickland, Radisky, Poulter, Le, Windsor, Lee, Koh,

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Disease relevance of alpha-hydroxyfarnesylphosphonic acid

Effects of hyperinsulinemia were completely abolished by the presence of 1 microM alpha-hydroxyfarnesylphosphonic acid, a potent inhibitor of farnesyltransferase [1].

High impact information on alpha-hydroxyfarnesylphosphonic acid

In both fibroblasts and adipocytes, the presence of perillyl alcohol blocked the ability of insulin to increase geranylgeranylation of Rab-4, whereas GGTI-298 and alpha-hydroxyfarnesylphosphonic acid were without effect, indicating that insulin activates GGTase II [2].
Insulin potentiated the effects of IGF-1, EGF, and PDGF on DNA synthesis in cells expressing the wild type insulin receptor, but this potentiation was inhibited in the presence of the FTase inhibitor, alpha-hydroxyfarnesylphosphonic acid [3].
Furthermore, endogenous NO, generated from NO synthase, activated ERK, and NOx-induced MAP kinase activation was effectively blocked by the farnesyl transferase inhibitor alpha-hydroxyfarnesylphosphonic acid [4].
On the basis of the recently reported crystal structure of FPT complexed with a CVIM peptide and alpha-hydroxyfarnesylphosphonic acid, site-directed mutagenesis of the FPT active site was performed so key residues that are responsible for substrate binding and catalysis could be identified [5].
This H(2)O(2)-induced Raf-1 kinase activation was also blocked by inhibition of Ras--PI3K signalling pathway using alpha-hydroxyfarnesylphosphonic acid and wortmannin [6].

Biological context of alpha-hydroxyfarnesylphosphonic acid

In an effort to characterize the catalytic site of rubber transferase, the effects of two types of protein farnesyltransferase inhibitors, several chaetomellic acid A analogs (2, 4-7) and alpha-hydroxyfarnesylphosphonic acid (3), on the ability of rubber transferase to add IPP to the allylic diphosphate initiator were determined [7].

Anatomical context of alpha-hydroxyfarnesylphosphonic acid

Using primary cultures of ovine pulmonary arterial endothelial cells we demonstrated that the NO donor SpermineNONOate, increased p21ras activity by 2.3-fold compared to untreated cells, and that the farnesyl-transferase inhibitor, alpha-hydroxyfarnesylphosphonic acid, reduced p21ras activity and significantly reduced inhibition of eNOS [8].

Gene context of alpha-hydroxyfarnesylphosphonic acid

Furthermore, B-58l and alpha-hydroxyfarnesylphosphonic acid, two inhibitors of Ras, did not block NF-kappaB activation [9].
NO-induced protection was blocked by the G protein inhibitor alpha-hydroxyfarnesylphosphonic acid (alphaHFP) 10 microM [10].

References

Hyperinsulinemia potentiates activation of p21Ras by growth factors. Leitner, J.W., Kline, T., Carel, K., Goalstone, M., Draznin, B. Endocrinology (1997) [Pubmed]
Insulin promotes phosphorylation and activation of geranylgeranyltransferase II. Studies with geranylgeranylation of rab-3 and rab-4. Goalstone, M.L., Leitner, J.W., Golovchenko, I., Stjernholm, M.R., Cormont, M., Le Marchand-Brustel, Y., Draznin, B. J. Biol. Chem. (1999) [Pubmed]
Effect of insulin on farnesyltransferase. Specificity of insulin action and potentiation of nuclear effects of insulin-like growth factor-1, epidermal growth factor, and platelet-derived growth factor. Goalstone, M.L., Leitner, J.W., Wall, K., Dolgonos, L., Rother, K.I., Accili, D., Draznin, B. J. Biol. Chem. (1998) [Pubmed]
Differential activation of mitogen-activated protein kinases by nitric oxide-related species. Lander, H.M., Jacovina, A.T., Davis, R.J., Tauras, J.M. J. Biol. Chem. (1996) [Pubmed]
Farnesyl protein transferase: identification of K164 alpha and Y300 beta as catalytic residues by mutagenesis and kinetic studies. Wu, Z., Demma, M., Strickland, C.L., Radisky, E.S., Poulter, C.D., Le, H.V., Windsor, W.T. Biochemistry (1999) [Pubmed]
Choline phosphate potentiates sphingosine-1-phosphate-induced Raf-1 kinase activation dependent of Ras--phosphatidylinositol-3-kinase pathway. Lee, M., Han, S.S. Cell. Signal. (2002) [Pubmed]
Protein farnesyltransferase inhibitors interfere with farnesyl diphosphate binding by rubber transferase. Mau, C.J., Garneau, S., Scholte, A.A., Van Fleet, J.E., Vederas, J.C., Cornish, K. Eur. J. Biochem. (2003) [Pubmed]
Nitric oxide activates p21ras and leads to the inhibition of endothelial NO synthase by protein nitration. Brennan, L.A., Wedgwood, S., Bekker, J.M., Black, S.M. DNA Cell Biol. (2003) [Pubmed]
Raf-independent and MEKK1-dependent activation of NF-kappaB by hydrogen peroxide in 70Z/3 pre-B lymphocyte tumor cells. Lee, M., Koh, W.S. J. Cell. Biochem. (2003) [Pubmed]
Role of G proteins and modulation of p38 MAPK activation in the protection by nitric oxide against ischemia-reoxygenation injury. Rakhit, R.D., Kabir, A.N., Mockridge, J.W., Saurin, A., Marber, M.S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]

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