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Squalene synthetase

Dioxolane derivatives, which are obtained from methoxybutenone and glycols and used as antifungicides, and squalene synthetase inhibitors have been described (94MI1). The reactions of mono- and oligosaccharides with... [Pg.226]

Figure26-2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG, 3-hydroxy-3-methylglutaryl x, cytokinin.) A farnesyl residue is present in heme a of cytochrome oxidase. The carbon marked with asterisk becomes C or C,2 in squalene. Squalene synthetase is a microsomal enzyme all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes. Figure26-2. Biosynthesis of squalene, ubiquinone, dolichol, and other polyisoprene derivatives. (HMG, 3-hydroxy-3-methylglutaryl x, cytokinin.) A farnesyl residue is present in heme a of cytochrome oxidase. The carbon marked with asterisk becomes C or C,2 in squalene. Squalene synthetase is a microsomal enzyme all other enzymes indicated are soluble cytosolic proteins, and some are found in peroxisomes.
The design of FTase inhibitors based on the structure of farnesyl pyrophosphate has been pursued with less intensity due to the possible nonselective effects of competing with other enzymes such as squalene synthetase that also accept farnesylpyrophosphate as substrate [3,4,9,10-12]. [Pg.122]

Further detailed study of the substrate specificity of yeast squalene synthetase has been reported (see Vol. 7, p. 130). The enzyme is very sensitive to changes in substrate. For example, 10,11-dihydrofarnesyl pyrophosphate was converted into 2,3,22,23-tetrahydrosqualene with only 60% of the efficiency of farnesyl pyrophosphate whereas 6,7-dihydro- and 6,7,10,11-tetrahydro-farnesyl pyrophosphates were not metabolized. The first of the two binding sites has a greater preference for farnesyl pyrophosphate and this accounts for the formation of the unsymmetrical squalene product when mixtures of farnesyl pyrophosphate and a modified substrate are used. The importance of the methyl groups, especially that at C-3, for binding is emphasized by the low efficiency of conversion of 3-desmethylfarnesyl, , -3-methylundeca-2,6-dien-l-yl (1), and E,E-7-desmethylfarnesyl pyrophosphates. The prenylated cyclobutanones (2) and (3)... [Pg.150]

RM Lawrence, SA Biller, OM Fryszman. Preparation of a-phosphonosulfinic squalene synthetase inhibitors. U.S. Patent 5447922, 1995. [Pg.172]

Zeneca reported the execution of solution-phase chemistry with a Zymark robotic system, thereby generating 50 quinuclidine analogues to test for squalene synthetase inhibition [38],... [Pg.73]

VOGELI, U., CHAPPELL, J., Induction of sesquiterpene cyclase and suppression of squalene synthetase activities in plant cell cultures treated with fungal elicitor, Plant Physiol., 1988, 88, 1291-1296. [Pg.249]

Squalene synthetase inhibitors, (IV), prepared by Hamanaka (5) were effective in the treatment of hypocholesterolemia, hypotriglyceridemia, and artherosclerosis. [Pg.267]

Biller, S.A., et al. (1991). The first potent inhibitor of squalene synthetase a profound contribution of an ether oxygen to inhibitor-enzyme interaction. J Am Chem Soc 113 8522-8524. [Pg.122]

The simple dioxolanone 309 has been prepared and has antidiabetic activity <2003W02550>, and the dioxolone structure 310 has been used as a pro-drug for pharmaceutically active amines R 2NH to which it is degraded in vivo <1995USP5466811>. Dioxolanone-containing compounds such as 311 have squalene synthetase and cholesterol synthetase inhibitory activity and can be used to treat hypercholesterolemia <2001JPP187789>. [Pg.881]

Ammonium salt (706) was used to mimic the topological and electrostatic properties of cation 707, which was suggested to be an intermediate in squalene biosynthesis706 turned out to inhibit squalene synthetase only in combination with pyrophosphate ... [Pg.1431]

A series of analogues, (4) and (5), of the precursors of squalene, in which the carbinol oxygen is replaced by a methylene group, inhibited the formation of squalene from [2- C]- and [S- HaJ-MVA by rat liver squalene synthetase. These phosphonophosphates also inhibited the biosynthesis of kaurene from MVA in a cell-free system from Ricinus communis, but the corresponding phosphonates were only weakly inhibitory. The formation of labelled squalene from a mixture of [2- C]MVA and [l- H]presqualene alcohol pyrophosphate by the squalene synthetase preparation was completely inhibited by the addition of (5) to the incubation... [Pg.181]

A phytoene synthetase that converts IPP into phytoene has been partially purified from tomato plastids. The complex, which had a molecular weight of ca. 200 000 dalton, was devoid of squalene synthetase activity and required Mn as a cofactor. ATP caused a six-fold stimulation in activity, and, as there was no evidence that it was otherwise involved, it may act as an allosteric effector. ... [Pg.182]

Biller, S.A., and Magnin, D.R., Preparation of a-phosphonoalkanoates as squalene synthetase inhibitors, Bristol-Myers Squibb, U.S. Patent Appl. US 5312814, 1994 Chem. Abstr., 122, 10300, 1995. [Pg.129]

The enzymes necessary for the conversion of famesyl pyrophosphate to squalene are called squalene synthetase . The enzymes necessary for the two reactions have not been resolved nor has either been purified to a significant extent, and it is not yet certain if the two reactions are catalyzed by two discrete entities. Squalene synthetase has an absolute requirement for a divalent cation, Mg " and Mn " being the best. A reduced pyridine nucleotide (NADH or NADPH) is required for the reduction of presqualene pyrophosphate to squalene. Yeast microsomes with Mn " and no reduced pyridine nucleotide will form dehydrosqualene instead [70]. The conversion of famesyl pyrophosphate to presqualene pyrophosphate is enhanced several-fold by the reduced pyridine nucleotide [71]. Also, some organic solvents as well as detergents increase this activity. [Pg.23]

Apparently, squalene synthetase is a relatively small microsomal protein. The enzyme was solubilized from yeast microsomes by deoxycholate. If detergent was then removed, the microsomal proteins aggregated. If instead, the preparation was centrifuged in a sucrose gradient containing detergent, squalene synthetase sedimented with an 20,w of 3.3 in contrast to the 14.2 20,w value reported earher. Centrifugation failed to resolve the two catalytic activities of squalene synthetase [72]. [Pg.23]

The deoxycholate-solubilized squalene synthetase was also chromatographed on Sephadex G-200 and a Stokes radius of 40 A was found for the enzyme. Again, the two catalytic activities were not resolved [72]. This value, along with the 20,w indicated a molecular weight of 55 000 for the protein(s). This contrasts with much higher values reported earlier. Inclusion of certain phospholipids in the tubes used... [Pg.23]

A variety of substrate analogs have been tested with microsomal squalene synthetase, and these have served to determine some of the specificity parameters for binding and reacting in this system. The requirement for the pyrophosphate moiety is absolute since farnesyl monophosphate does not participate in the reaction. It is not known if the divalent cation requirement is for binding and/or catalysis [67]. [Pg.24]

The conversion of famesyl pyrophosphate to squalene marks the transition from water-soluble to water-insoluble intermediates in the biosynthesis of cholesterol. When the effect of liver cytosol or SCPj on the conversion of famesyl pyrophosphate to squalene was investigated, neither rat liver cytosol nor partially purified SCPj had any significant effect on this conversion [23]. Therefore, microsomal squalene synthetase performs its catalytic function without responding to the mediating effect of any specific soluble protein. [Pg.75]

The mevalonate pathway in the cytosol is responsible for biosynthesis of sterols, sesquiterpenes, and triterpenoids. After conversion of mevalonic acid to isopentenyl pyrophosphate, three C5 units can be joined head to tail to produce a C15 compound, famesyl pyrophosphate. Two famesyl pyrophosphates are then united head to head to form squalene, the progenitor of the C30 isoprenoids from which sterols are derived. The plant squalene synthetase, like its mammalian homologue, is found in the ER and the reaction proceeds via a presqualene pyrophosphate intermediate (Chapter 14). In the last step prior to cyclization, squalene is converted to squalene 2,3-epoxide. [Pg.115]

Steroids are members of a large class of lipid compounds called terpenes. Using acetate as a starting material, a variety of organisms produce terpenes by essentially the same biosynthetic scheme (Fig. 8). The self-condensation of two molecules of acetyl coenzyme A (CoA) forms acetoacetyl CoA. Condensation of acetoacetyl CoA with a third molecule of acetyl CoA, then followed by an NADPH-mediated reduction of the thioester moiety produces mevalonic acid [150-97-0] (72). Phosphorylation of (72) followed by concomitant decarboxylation and dehydration processes produce isopentenyl pyrophosphate. Isopentenyl pyrophosphate isomerase establishes an equilibrium between isopentenyl pyrophosphate and 3,3-dimethylallyl pyrophosphate (73). The head-to-tail addition of these isoprene units forms geranyl pyrophosphate. The addition of another isopentenyl pyrophosphate unit results in the sesquiterpene (C15) famesyl pyrophosphate (74). Both of these head-to-tail additions are catalyzed by prenyl transferase. Squalene synthetase catalyzes the head-to-head addition of two achiral molecules of famesyl pyrophosphate, through a chiral cyclopropane intermediate, to form the achiral triterpene, squalene (75). [Pg.426]


See other pages where Squalene synthetase is mentioned: [Pg.426]    [Pg.65]    [Pg.226]    [Pg.150]    [Pg.1549]    [Pg.426]    [Pg.2033]    [Pg.2045]    [Pg.982]    [Pg.984]    [Pg.986]    [Pg.988]    [Pg.991]    [Pg.182]    [Pg.132]    [Pg.147]    [Pg.150]    [Pg.475]    [Pg.23]    [Pg.193]    [Pg.193]    [Pg.223]    [Pg.770]    [Pg.248]   
See also in sourсe #XX -- [ Pg.982 ]

See also in sourсe #XX -- [ Pg.455 , Pg.485 ]




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