Farnesyl pyrophosphate synthetases

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... 

Manganese acts as a cofactor of mevalonate kinase and farnesyl pyrophosphate synthetase. Mevalonate kinase and possibly one other manganese-activated enzyme are necessary for the formation of mevalonate from acetate (3). Farnesyl pyrophosphate synthetase acts to add one 5-carbon unit to geranyl pyrophosphate to make farnesyl pyrophosphate (4) (Figure 1). 

Two isoenzymes of isopentenyl pyrophosphate isomerase (EC 5.3.3.2) were found by Ogura et in pumpkin. These workers also studied farnesyl pyrophosphate synthetase (EC 2.5.1.1) from this plant in an attempt to define... 

Farnesyl pyrophosphate synthetases have been isolated from yeast, Phycornyces blakesleanus, and livers of pig, chicken [6] and man [58]. All of the transferases have molecular weights of 75000-85000 and are comprised of two apparently identical subunits. These enzymes have relatively broad activity maxima at neutral pH, and the values of substrates are around 0.5 jaM. Evidence has been presented for the participation of an arginine and the presence of an essential sulfhydryl in the enzyme from human liver [57,58]. The chicken liver enzyme apparently lacks these features [6]. 

The enzyme, farnesyl pyrophosphate synthetase (prenyl transferase), is responsible for the condensation of (4.14) with (4.15) to give geranyl pyrophosphate (4.41). The same enzyme mediates addition of a further molecule of (4.14) to (4.41) yielding 2- ran5-farnesyl pyrophosphate (4.19). This is the basic unit for the elaboration of the structurally diverse sesquiterpenes. The results obtained on biosynthesis are as interesting as the sesquiterpene structures. The 2 cis... 

Ethylbut-3-enyl pyrophosphate also acts" as a substrate for farnesyl pyrophosphate synthetase with dimethylallyl pyrophosphate or geranyl pyrophosphate as the starter unit to afford homologues of farnesyl pyrophosphate. 

Specificity of farnesyl pyrophosphate synthetase from pumpkin fruit with regard to the allylic pyrophosphate revealed that disubstitution at C-3 is... 

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]. 

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)... 

The addition of the appropriate keteniminium salts to the olefin (119) gave the cyclobutanones (120a and 120b), which were weak inhibitors of yeast squalene synthetase compared with farnesyl pyrophosphate. 

The condensation of dimethyallyl pyrophosphate, an isomerization product of isopentenyl pyrophosphate, with isopentenyl pyrophosphate, has been shown to yield geranyl pyrophosphate (Lynen et al., 1959). The enzyme, isopentenyl pyrophosphate isomerase, has been described (Agranoff et al., 1960). Geranyl pyrophosphate may condense with another molecule of isopentenyl pyrophosphate to yield farnesyl pyrophosphate. The enzyme farnesyl synthetase had been isolated by Lynen et al. (1959). The reductive dimerization of two molecules of... 

The third phase of cholesterol biosynthesis (Fig. 20.20) involves the condensation of two molecules of farnesyl-pyrophosphate, yielding squalene via the enzyme squa-lene synthetase. 

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]. 

---