Disease relevance of C09094

• Geranylgeraniol regulates negatively caspase-1 autoprocessing: implication in the Th1 response against Mycobacterium tuberculosis [1].
• We examined the antibacterial activities against Staphylococcus aureus of three diterpenes, namely, geranylgeraniol, teprenone, and phytol, by using a broth dilution with shaking method to identify the effects of diterpenes with long aliphatic carbon chains [2].
• Recently, it has been shown that free geranylgeraniol (GG-OH) and farnesol (F-OH) can be utilized by C6 glioma cells for protein isoprenylation [3].
• Furthermore, when cells were treated with either alendronate alone or in combination with Z-VAD-FMK for 24 or 48 h, subsequent addition of geranylgeraniol, which restores geranylgeranylation, returned bone resorption to control levels [4].
• Four chemically different bacteriochlorophylls (Bchls) a esterified with geranylgeraniol, dihydrogeranylgeraniol, tetrahydrogeranylgeraniol, and phytol have been detected by high-pressure liquid chromatography in cell extracts from Rhodopseudomonas sphaeroides and Chromatium vinosum [5].

High impact information on C09094

• We conclude that cholesterol turnover in brain activates the mevalonate pathway and that a constant production of geranylgeraniol in a small subset of neurons is required for LTP and learning [6].
• Brain cholesterol turnover required for geranylgeraniol production and learning in mice [6].
• This inhibition is prevented by exogenous geranylgeraniol, probably required for prenylation of GTP binding proteins that control cytoskeletal reorganization, vesicular fusion, and apoptosis, processes involved in osteoclast activation and survival [7].
• This phenomenon was accompanied by a relative increase of p21(ras) farnesylation and by a decrease of the ratio between the amounts of geranylgeraniol and farnesol bound to prenylated proteins [8].
• The inhibitory effect of lovastatin on PMA-stimulated leukocyte adhesion was reversed by co-incubation with geranylgeraniol, but not with farnesol, with concurrent reversal of the inhibition of protein prenylation as shown by protein RhoA geranylgeranylation [9].

Chemical compound and disease context of C09094

• Biphasic effects of geranylgeraniol, teprenone, and phytol on the growth of Staphylococcus aureus [2].
• The addition of geranylgeraniol, an intermediate of the mevalonate pathway, suppressed the ZOL-induced apoptosis, suggesting that the cytotoxic effects of ZOL in osteosarcoma cells were mediated by the mevalonate pathway [10].

Biological context of C09094

• We have used specific inhibitors for farnesyltransferase (FTase) and geranylgeranyltransferase (GGTase) I as well as combinations of lovastatin with geranylgeraniol (GGOH) or farnesol (FOH) to investigate the role of protein prenylation in platelet-derived growth factor (PDGF)-induced PDGF receptor tyrosine phosphorylation [11].
• Methyl iodide hydrolysis resulted in the release of covalently bound farnesol, geranylgeraniol, phytol, and some unidentified isoprenoid compounds from mevalonate-labeled proteins [12].
• In a previous study, we showed that geranylgeraniol (GGO) is a potent inducer of apoptosis in human leukemia cells, including HL60 promyelocytic leukemia cells [13].
• Besides GGA, 4,5-didehydro GGA, 14,15-dihydro GGA, and 2,3-dihydro GGA were also active to induce cell death in HuH-7 cells, while 4,5-didehydro-10,11, 14,15-tetrahydro GGA, 4,5,8,9-tetrahydro GGA, farnesoic acid, and geranylgeraniol were inert [14].
• Furthermore, geranylgeraniol could prevent inhibition of prenylation, induction of apoptosis, and cell-cycle arrest in response to RIS, but not inhibition of Rab prenylation and apoptosis induced by 3-PEHPC, consistent with specific inhibition of Rab geranylgeranyl transferase by 3-PEHPC [15].

Anatomical context of C09094

• Finally, the effect of geranylgeraniol on neurite outgrowth is prevented by Y-27632, an inhibitor of RhoA kinase [16].
• We conclude that lipophilic vastatins inhibit TF expression in macrophages, and because this effect is prevented by mevalonate and geranylgeraniol, a geranylgeranylated protein plays a crucial role in the regulation of TF biosynthesis [17].
• Activation of protein kinase C prevents induction of apoptosis by geranylgeraniol in human leukemia HL60 cells [13].
• Farnesol and geranylgeraniol modulate the structural properties of phosphatidylethanolamine model membranes [18].
• This inhibitory action by alpha-T3 on TNF-alpha-induced monocyte adhesion was shown to be NF-kappaB dependent and was interestingly reversed with co-incubation with farnesol and geranylgeraniol, suggesting a role for prenylated proteins in the regulation of adhesion molecule expression [19].

Associations of C09094 with other chemical compounds

• Taken together, our results suggest that inhibition of geranylgeraniol synthesis causes sterol-dependent neurite outgrowth in a process that is mediated by inhibition of RhoA signaling [16].
• We examined the apoptosis-inducing ability of VK2 (menaquinone 3 (MK3), MK4 and MK5) and its derivatives such as phytonadione (VK1), as well as polyprenylalcohols with side chains of various lengths including farnesol (C15-OH; FO), geranylgeraniol (C20-OH; GGO), and geranylfarnesol (C25-OH; GFO) toward leukemia cells in vitro [20].
• Induction of apoptosis was mainly via inhibition of the mevalonate (MVA) pathway, as addition of the MVA pathway intermediary geranylgeraniol inhibited the induction of apoptosis by doxorubicin followed by zoledronic acid [21].
• The samples of chlorophylls were then hydrolysed with alkali to obtain phytol and geranylgeraniol, which were converted into the corresponding trimethylsilyl derivatives and analysed by gas chromatography-mass spectrometry [22].
• 4 The inhibitory effect of alendronate on IkappaB phosphorylation and degradation was not attenuated by the exogenous addition of geranylgeraniol to replenish the cytosolic isoprenyl lipid substrate [23].

Gene context of C09094

• The mechanism of geranylgeraniol-induced apoptosis involves activation, by a caspase-3-like protease, of a c-jun N-terminal kinase signaling cascade and differs from mechanisms of apoptosis induced by conventional chemotherapeutic drugs [24].
• A second amino acid motif found in mGBP-2 is a potential C-terminal site for isoprenoid modification, called a CaaX sequence. mGBP-2 is prenylated, as detected by [3H]mevalonate incorporation, when expressed in COS cells and preferentially incorporates the C-20 isoprenoid geranylgeraniol [25].
• GGTI-2166 inhibited TRAP activity induced by RANKL or TNF-alpha in both cell cultures and prevented the incorporation of [3H]all-trans geranylgeraniol into prenylated proteins in RAW cells [26].
• Among these compounds, geranylgeraniol with 4 prenyl units, and MK-2 with 2 prenyl units, showed the highest cytotoxic activity against human oral tumor cell lines (HSC-2, HSG), without induction of internucleosomal DNA fragmentation [27].
• Shorter (C10, geraniol) and longer (C20, geranylgeraniol) isoprenols were inactive [28].

References