Farnesyl phosphates

FIGURE 1.4 Proposed biosynthetic route for the biosynthesis of (A) squalene oxide (squalene-2,3-oxide) via the isoprenoid pathway and (B) triterpene saponins of the dammarane-type and oleanane-type from squalene oxide. PP, diphosphate group GPS, geranyl phosphate synthase FPS, farnesyl phosphate synthase NADPH, nicotinamide adenine dinucleotide phosphate. 

Steroids are synthesised in organisms via complex mechanisms from isoprene units, isopentenyl diphosphate and dimethylaUyl diphosphate, which first yield geranyl diphosphate. Reaction with another molecule of isopentenyl diphosphate gives an important intermediate, farnesyl diphosphate (Figure 3.10). Two molecules of farnesyl phosphate give rise to triterpenic hydrocarbon squalene (3-81), which in the body of animals yields triterpenic alcohol lanosterol (3-92) and the triterpenic alcohol cycloartenol (3-93) in plants. 

Ki, phytyl side chain) two vitamins K with six and seven isoprene residues in the side chains (and six or seven double bonds) have also been discovered. The chain is built analogously to the condensation, forming farnesyl phosphate. In the bioassay, menadione (2-methylnaphthoquinone) is also active, presumably because it is converted to vitamin K2 in the organism (proof with C -menadione). 

Since a-bisabolol, in contrast to a-terpineol, has two asymmetric centers, the interesting question arises as to whether there is stereoselec-tively in the nucleophilic capture step. If there were a net anti addition of the electrophile (Ci) and the nucleophile (H2O) across the 6,7-double bond (as required for a configurationally stable non-classical carbonium ion intermediate), cis, trun -farnesol and trans-nttolidol should cyclize to one diastereomeric a-bisabolol (4R, 8R-55-OH and its enantiomer). Rittersdorf and Cramer have looked into the matter in a study of hydrolysis of cis, /ran -farnesyl phosphate (51-OP), trans-ntrolidyi phosphate (53-OP), and cw-nerolidyl phosphate (58-OP) (79). 

The inositol polyphosphate 5-phosphatases belong to a family of enzymes that terminate the signals generated by inositol lipid kinases and PLC. To date, two major types of 5-phosphatase have been identified, both of which share a common 5-phosphatase domain of approximately 300 amino acids, with several highly conserved motifs. Type-I enzymes are 43-65 kDa and preferentially hydrolyze 1(1,4,5)P3 and 1(1,3,4,5)P4, with the attendant formation of I(1,4)P2 and 1(1,3,4)P3, but have little or no activity towards membrane-bound phosphoinositides. The pro-totypic form of a type-15-phosphatase is a 43 kDa protein that is post-translationally modified by farnesylation of the carboxyl terminus CAAX motif this modification juxtaposes the enzyme with the membrane. Type-II enzymes are larger (75-160 kDa) and will hydrolyze both water-soluble inositol phosphates and lipids that... 

This enzyme [EC 2.5.1.10], also known as farnesyl-di-phosphate synthase, catalyzes the reaction of geranyl diphosphate with isopentenyl diphosphate to produce trans,trans-farnesyl diphosphate and pyrophosphate (or, diphosphate). Some forms of this enzyme will also utilize dimethylallyl diphosphate as a substrate. However, the enzyme will not accept larger prenyl diphosphates as an efficient substitute for geranyl diphosphate. 

P 2 -deoxyadenosine 5 -diphosphate + trans-farnesyl triphosphate S 2 -deoxy-adenosine 5 phosphate -I- trans-farnesyl diphosphate <1> (<1>... 

Shechter, I. Phosphate transfer from trans-farnesyl triphosphate to AMP in Gibberella fujikuroi. Biochim. Biophys. Acta, 362, 233-244 (1974)... 

If sterol content and conformation are so important for membrane stability, we should study the biosynthesis of sterols (Figure 3). The first enzyme in terpenoid biosynthesis is the 3-Hydroxy-3-Methyl-Glutary1-Coenzyme A-reductase (HMG-CoA-reductase) that catalyzes the synthesis of mevalonate. Two phosphorylations and decarboxylation of mevalonate lead to isopentenylpyrophosphate, the basic C -unit in sterol synthesis. Isopentenylpyrophosphate reacts with its isomer, the dimethylally1-pyrophosphate, in a head/tail-reaction to geranyl-pyrophosphate reaction with another C -unit leads to farnesyl-pyro-phosphate, that dimerizes in a tail/tail-reaction to squalene. After expoxidation of its A -double bond, squalene cyclizes to lano-... 

Figure 27 Four possible pathways for ABA biosynthesis. Open and closed circles show the 13C label from [1-13C]-d-glucose in the mevaloic acid pathway and the MEP pathway, respectively. DAP, dihydroxyacetone phosphate DXP, 1-deoxy-xylulose-5-phosphate FDP, farnesyl diphosphate GAP, glyceraldehyde-3-phosphate GGDP, geranylgeranyl diphosphate HMG-CoA, 3-hydroxy-3-methylglutaryl CoA IDP, isopentenyl diphosphate MEP, 2-C-methyl-D-erythritol-4-phosphate.

Figure 5 (a) Chaetomellic acid A is a novel dicarboxylate-containing natural product that is thought to mimic farnesyl pyrophosphate and thus to inhibit the enzyme FTPase. This compound can exist in either the dicarboxylate or anhydride form, (b) As peptides that contain aromatic oxamic acids are good inhibitors of tyrosine kinase p56 SH2 domains, it is believed that the oxamic acid moiety may mimic the phosphate group, (c) A symmetric 3,5-disubstituted benzoate analog of S3P (substrate) and EPSP (product) inhibits EPSPS. 

Synthesis of Phosphoric Acids and their Derivatives. - Among various approaches to phosphate esters the phosphorylation of phenols with dialkyl cyanophosphonate and the synthesis of triaryl phosphates under phase-transfer conditions are worthy of mention. Mixed trialkyl phosphates are also reported to be formed by brief cathodic electrolysis of the reaction of dialkyl phosphonates with aromatic aldehydes and ketones, presumably by rearrangement of the initial a-hydroxy compounds. Further reports have appeared of the generation of metaphosphates by various methods. The synthesis of analogues 1 of famesyl pyrophosphate which incorporate photoactive esters has been reported both compounds are competitive inhibitors of farnesyl transferase. 

Two simpler chromans obtained from orcinol and farnesyl diphenyl phosphate have been investigated (ref. 28). These have been assigned the structures shown and the less polar (B), having a more sterically hindered hydroxyl group, proved to be identical with an acid-catalysed rearrangement product of grifolin (ref. 30). 

Cellular metabolites derived from mevalonic acid are required for cell proliferation. Cholesterol Is an essential component of cell membranes, farnesyl pyrophosphate is required to covalently bind to intracellular proteins and modify their function, ubiquinone is required for mitochondrial electron transport, and dolichol phosphates are required for glycoprotein synthesis. 

Farnesyl pyrophosphate (Fig. 30.2) is an intermediate in the biosynthesis of cholesterol, ubiquinone, and dolichol phosphates. Based on their site of action, HMGRis will decrease the availability of all four of these compounds and, thus, decrease cell proliferation. Potential applications of this antiproliferative effect include the prevention of restenosis following angioplasty, prevention of glomerular injury in renal disease, treatment of malignant disease, and prevention of organ transplantation rejection (40). 

Fig. 8.16 Pathways for the production of hydroxylated carotenoids in . coli. Isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP) are produced via internal methylerythritol phosphate (MEP) pathway and FPP synthase. CrtE GGPP synthase, CrtB phytoene synthase, CrtI phytoene dehydrogenase, LycB lycopene p-cyclase, LycE lycopene e-cyclase...

---