Farnesyl side chains

Tocopherols Tocopherols are widely distributed in nearly all vegetable oils but not in animal fats. Their basic structure consists of the hypothetic tocol molecule, a chromanol structure with a farnesyl side chain, substituted by one, two, or three methyl groups in the positions 5, 7, or 8. (Figure 5). A homologous... 

As already discussed, the model proposed by Tsukihara et alP depends on the so-scalled H-pathway of proton transfer and on the function of an aspartic acid that is not conserved in the bacterial oxidases. This model also depends crucially on the formyl group and on the hydroxyethyl farnesyl side chain of heme a. Many proton-pumping bacterial oxidases, such as cytochrome boj, from E. coll, have replaced heme a with a protoheme (heme B) that lacks both the formyl and the farnesyl side chain. Therefore, this model is restricted to heme a - containing oxidases, and implies different mechanisms of proton translocation in different members of the heme-copper oxidase superfamily. 

The flesh of Chroogomphus helveticus contains considerable quantities of a second isoprenoid quinone, helveticone (221) 606). In the mass spectrum helveticone exhibited characteristic ions arising by fragmentation of a farnesyl side chain and the structure (221) was corroborated by comparison of this and other spectroscopic data with those of the isoprenologue (222). 

Phytyl chains often take the place of farnesyl side chains. The alcohol phytol has already been mentioned in connection with chlorophyll, where it is esterified to one of the carboxyl groups. Phytol is linearly composed of four isoprene units and is hydrogenated extensively in fact, it retains only one double bond near the primary alcohol group. 

FIGURE 9.19 Proteins containing the C-terminal sequence CAAX can undergo prenylation reactions that place thioether-linked farnesyl or geranylgeranyl groups at the cysteine side chain. Prenylation is accompanied by removal of the AAX peptide and methylation of the carboxyl group of the cysteine residue, which has become the C-terminal residue. 

The substrate specificity of farnesyl pyrophosphate synthetase has been studied using 3-methyl-2-aIkenyl pyrophosphates (90) as models. When (90) bears a large side-chain i.e. R = C4H9), the reaction with isopentenyl pyrophosphate ceases after the formation of (91) and this reaction has been... 

Menaquinone. The incorporation of [2- C]mevalonate and [2- C]-2-methyl-l,4-naphthoquinone into MK-4, normally considered a bacterial quinone, has been demonstrated in marine invertebrates such as crabs and starfish." Incorporation into 2,3-epoxy-MK-4 (163) was also observed. Cell-free extracts have been prepared from Escherichia coli which catalyse the conversion of o-succinylbenzoic acid (164) into l,4-dihydroxy-2-naphthoic acid (165) and menaquinones. In the presence of farnesyl pyrophosphate the major menaquinone produced was MK-3. Genetic studies with mutants of E. coli K12 that require (164) offer support for the generally accepted pathway for MK biosynthesis via (164) and (165)." The enzyme system that catalyses the attachment of the polyprenyl side-chain to 1,4-dihydroxy-2-naphthoic acid to form demethylmenaquinone-9 (166) has been isolated from E. colU ... 

Several papers report new findings on ubiquinone biosynthesis. A mitochondrial membrane-rich preparation from baker s yeast can convert 4-hydroxybenzoate and isopentenyl pyrophosphate into the ubiquinone precursor 3-all-trans-hexaprenyl-4-hydroxybenzoate (234). Details of the cell-free system are presented. With preformed polyprenyl pyrophosphates, the system catalysed the polyprenylation of several aromatic compounds, e.g. methyl 4-hydroxybenzoate, 4-hydroxybenzaldehyde, 4-hydroxybenzyl alcohol, and 4-hydroxycinnamate. No evidence was obtained for the involvement of 4-hydr-oxybenzoyl-CoA or 4-hydroxybenzoyl-S-protein in the reaction. With shorter-chain prenyl pyrophosphates a shorter prenyl side-chain was introduced, e.g. geranyl and farnesyl pyrophosphates gave products with a 3-diprenyl and 3-triprenyl side-chain respectively. A crude enzyme preparation from E. coli... 

Overhauser effect experiments coordination of the cysteine side-chain to the Zn ion promotes the conformational change in the peptide backbone. Moreover, differences in the conformation binding mode of peptides and peptidomimetics is one of the bases for selective farnesylation (208). 

The presence of a nitrogen-containing side chain facilitates interaction with the catalytic site of FPPS, an enzyme in the metabolic pathway that is required for the production of the isoprenoid hpids farnesyl diphosphate and geranylgeranyl diphosphate, essential metabolites for posttranslational protein prenylation [5, 8]. Inhibiting the prenylation of guanosine triphosphate-binding proteins such as Ras, Rho, and Rac disrupts the normal cellular signal transduction that is required for osteoclast function and survival [5]. 

Biosynthetic studies showed that the aromatic ring was formed from a poly-ketide whilst the side chain was derived from the mevalonate terpenoid pathway. The C-5 O-methyl and C-4 methyl groups were derived from methionine. The high incorporation of 4,6-dihydroxy-2,3-dimethyl-[l- C]benzoic acid (4.37) suggested that the methylation at C-4 occurred at the polyketide stage prior to the formation of the phthalide. 5,7-Dihydroxy-4-methyl-[7- C]phthalide (4.38) and its 6-farnesyl analogue were also incorporated eiSciently into mycophenolic acid. The farnesyl precursor was detected as a metabolite of P. brevi-compactum and shown to be formed from 5,7-dihydroxy-4-methyl-[7- C]phthalide by a trapping... 

The enzymes responsible for the conversion of lanosterol to cholesterol, as were those for the conversion of farnesyl pyrophosphate to squalene and lanosterol, are all integral membrane-bound proteins of the endoplasmic reticulum. Many have resisted solubiUzation, some have been partially purified, and several have been obtained as pure proteins. As a consequence, much of the enzymological and mechanistic studies have been done on impure systems and one would anticipate a more detailed and improved understanding of these events as more highly purified enzymes become available. Many approaches have been taken to establish the biosynthetic route that sterols follow to cholesterol. Some examples are synthesis of potential intermediates, the use of inhibitors, both of sterol transformations and of the electron transfer systems, and by isotope dilution experiments. There is good evidence that the enzymes involved in these transformations do not have strict substrate specificity. As a result, many compounds that have been found to be converted to intermediates or to cholesterol may not be true intermediates. In addition, there is structural similarity between many of the intermediates so that alternate pathways and metabolites are possible. For example, it has been shown that side-chain saturation can be either the first or the last reaction in the sequence. Fig. 21 shows a most probable series of intermediates for this biosynthetic pathway. 

C.,5 side chains of the isopentenyl, geranyl and farnesyl type repectively have been examined in this connection. 

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