Geranylgeranyl pyrophosphate synthesis

Although sterols like cholesterol are not synthesized de novo by parasitic flatworms, they do possess an active mevalonate pathway (Fig. 20.3) (reviewed in Coppens and Courtoy, 1996). This pathway has been studied in 5. mansoni, and all available evidence indicates that it is similar to the lipid metabolism seen in F. hepatica. The mevalonate pathway was shown to be used by 5. mansoni for the synthesis of dolichols for protein glycosylation, of quinones as electron transporters in the respiratory chain and of farnesyl and geranylgeranyl pyrophosphates as substrates for the isopreny-lation of proteins (Chen and Bennett, 1993 Foster et a/., 1993). A key enzyme in the mevalonate pathway is 3-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) and it was shown that the schistosomal enzyme differs from the mammalian type, both structurally and in its regulatory properties (Rajkovic et ai, 1989 Chen et at., 1991). Farnesyl pyrophosphate plays a key role in the mevalonate pathway as it is the last common substrate for the synthesis of all end products (Fig. 20.3). As mentioned already, the branch leading from farnesyl pyrophosphate via squalene to cholesterol is not operative in parasitic flatworms, whereas the other branches are active, at least in S. mansoni and probably also in F. hepatica and FI. diminuta. 

The prenyl transferase from avian liver has been crystallized,40 and was found to be a dimer of molecular weight 86 000 dalton the subunits could not be resolved by SDS electrophoresis. The enzyme catalysed the formation of FPP from IPP and either DMAPP or GPP, and this was accompanied by the synthesis of small amounts of geranylgeranyl pyrophosphate (GGPP). This is the first stable crystalline enzyme of the steroid and terpenoid pathways to be prepared. 

Maynor, M., Scott, S. A., Rickert, E.A., and Gibbs, R.A. (2008). Synthesis and evaluation of 3- and 7-substituted geranylgeranyl pyrophosphate analogs. Bioorg Med Chem Lett 18 1889-1892. 

Biosynthetic pathways very rarely seem to take advantage of the concept of bi-directional synthesis - plausibly for the same problems of terminus differentiation that synthetic chemists have to face in the case of (typically) non-sym-metric targets -, although there are related examples such as in the elaboration of geranylgeranyl pyrophosphate on the path to carotenes. 

The five-carbon compound used for the synthesis of ter-penes is isopentenyl pyrophosphate. The reaction of dimethylallyl pyrophosphate (formed from isopentenyl pyrophosphate) with isopentenyl pyrophosphate forms geranyl pyrophosphate, a 10-carbon compound. Geranyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form farnesyl pyrophosphate, a 15-carbon compound. Two molecules of farnesyl pyrophosphate form squalene, a 30-carbon compound. Squalene is the precursor of cholesterol. Farnesyl pyrophosphate can react with another molecule of isopentenyl pyrophosphate to form geranylgeranyl pyrophosphate, a 20-carbon compound. Two geranylgeranyl pyrophosphates join to... 

Formation of Geranylgeranyl Pyrophosphate Formation of Prephytoene Pyrophosphate Formation of Phytoenes Acyclic Carotenoids Alicyclic Carotenoids Oxygenated Carotenoids Site of Synthesis Chemosystematic Studies Carotenoids in Algae Cartenoids in Fungi Biological Activity... 

On the basis of the configuration of the four chiral centers, a biosynthetic pathway can be proposed with phytol as precursor. In this mechanism, two phytyl chains would condense, probably as pyrophosphate derivatives, to produce the prelycopadiene pyrophosphate (46), which would be converted to lycopadiene (45) by addition of a hydride ion to a rearranged cyclopropylcation. An intermediate analogous to (46) is known to occur in the synthesis of phytoene, the precursor of the carotenoids in this latter case two geranylgeranyl pyrophosphates are condensed (45). In another possible pathway, lycopadiene (45) would merely result from reduction of phytoene. 

At first glance, it is difficult to recognize the gibberellins as diter-penes. However, any element of doubt about this has been dispelled by isotope experiments in vivo and in a cell-free system. In the fluid endosperm of the wild cucumber Echinocystis macrocarpa the following synthetic pathway has been demonstrated (Fig. 85) geranylgeranyl pyrophosphate—(—) kaurene—(—) kauren-19-ol —gibberellin A5. Presumably the synthesis then proceeds via Aj to gibberellic acid. 

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