Famesol pyrophosphate

The next step in the biosynthesis of steroids features an unusual head-to-head coupling reaction of two famesol pyrophosphates (OPP, not shown in diagram) to afford the alicyclic triterpene squalene 3-1, a compound found in shark liver oil (Scheme 2.3). Note that this product is in fact symmetrical about the newly formed bond. The next reaction in the sequence, which has only recently been uncovered, comprises oxidation of the terminal double bond to an epoxide. Opening of the oxirane leads to a domino-like series of ring-closing reactions and also concomitant migration of methyl groups. This chain reaction can be, and in fact has been, duplicated in the laboratory in the absence of enzymes. This series of reactions leads to the hypothetical steroidal carbocation 3-2. 

Aqueous hydrolysis of geranyl and farnesyl pyrophosphates forms the monoterpene geraniol and the sesquiterpene famesol, respectively. 

Hydrolysis of the pyrophosphate ester group converts famesyl pyrophosphate to the corresponding alcohol farnesol (see Figure 26.6 for the stmcture of famesol). 

The biosynthesis of the juvenile hormones is not yet fully known. Their similarity to famesol, an intermediate product in the biosynthesis of steroles in mammals, leads one to assume that their formation is analogous to that of farnesol. This obvious assumption seems to be supported by publications that have appeared in the early 1970s. Barnes and Goodfellow (1971) showed that isoprenoid biosynthesis in the larva of Sarcophaga bullata proceeds with the participation of mevalonate kinase. This enzyme regulates the formation of mevalonic acid pyrophosphate, an important intermediate product in steroid biosynthesis of mammals. Isopentenyl pyrophosphate, the C, unit of isoprenoid biosynthesis, is formed from mevalonic acid pyrophosphate by decarboxylation and, with the participation of ATP, by dehydration. 

At the same time, several findings have been published in the literature which indicate that juvenile hormone synthesis does not follow the seemingly obvious path. Metzler et al. found that of the presumed precursors of juvenile hormones only acetate and the ester methyl group arising from methionine are incorporated, while mevalonate, famesol and famesyl pyrophosphate are not (Metzler et al., 1971 Rodc-Goval et al., 1975). 

From FDP, a phosphatase or pyrophosphatase catalyzes the removal of the pyrophosphate group, generating famesol (Fig. (5)). The next two steps, oxidation of this alcohol to an aldehyde (famesal), then a carboxylic acid (famesoic acid), are catalyzed by one or two NAD+-dependent dehydrogenase(s) [63]. In the cockroach, D. punctata, methylation of... 

A problem in the use of dimethylallyl pyrophosphate (3) is its instability. In a study of this problem the half-life of this substance was examined over a range of pH values and temperatures. Both cis- and trans-prenyl pyrophosphates (4 n = 0, 1, or 2) occur in Pinus radiata. Their biosynthesis from [2- C,3R,4K- H]-mevalonic acid proceeded with retention of tritium whereas with [2- C,3K,4S- HJmevalonic acid tritium was lost [except in the case of isopentenyl pyrophosphate (4 n = 0)]. The authors suggest that since they could not detect an isomerase, there may be a cis- and a trans-prenyl transferase both of which eliminate the label derived from [4S- H]mevalonic acid. However, compart-mentalization may have resulted in the isomerase not being available to the administered monoterpenoids, although it may act on geranyl pyrophosphate formed in situ. The absence of 6-cis-famesol derivatives tends to support this idea. Further work on this system again produced no evidence for isomerization or metabolism of [l- H]nerol pyrophosphate to 2-rrans-6-c(s-farnesyl pyrophosphate. 

Sesquiterpenes (sesquiterpenoids). A structurally highly diverse class of terpenoids with 15 carbon atoms skeleton derived biosynthetically from famesyl pyrophosphate (FPP) ( famesol, isoprene rule, ter-penes). More than 70 different ring systems are formed by enzyme-catalyzed cyclization of the linear parent structure these cyclic structures can be further modified by 1,2- and 1,3-hydride shifts, renewed cycliza-tions, hydroxylations, and other subsequent reactions. S. are widely distributed in plants, fiingi, and animals but are less common in bacteria. Specific biosynthetic routes are often characteristic for certain organisms. Thus, basidiomycetes preferentially use humulene as the basis for the syntheses of protoilludanes, illu-danes, lactaranes, hirsutanes, and related S. skeletons. Individual S. systems are also known for liverworts and marine organisms. In addition, liverworts often contain the optical antipodes of S. known from plants. 

Most acyclic sesquiterpenes are derived from famesol and nerolidol (7) or from the corresponding pyrophosphate esters. Although the number of acyclic sesquiterpenes is relatively small, Z- and -famesol (5 and 6), nerolidol (7), and the corresponding olefins are relatively common in essential oils. The famesenes and a few other compounds, such as 3-sinesal (8), are derived in a straightforward manner, but most acyclic sesquiterpenes are more complex in origin (Fig. 21.4). 

S. are biosynthesized from famesylpyrophosphate (see Terpenes). Acyclic S., e.g. famesol, are formed by hydrolytic removal of the pyrophosphate group. TTie various types of cyclic S. are formed by elimination of the pyrophosphate residue to form an unstable cation, which stabilizes by loss of a proton. 

Just as geraniol (63) is the precursor for all the monoterpenoids, famesol (111) is the precursor for all the sesquiterpenoids. Its pyrophosphate is synthesized in nature by the addition of isopentenyl pyrophosphate (66) to geranyl pyrophosphate (68) as shown in Figure 5.14 and hydrolysis of that gives famesol. Incipient heterolysis of the carbon-oxygen bond of the phosphate gives the nascent... 

Figure 5.22 shows a tiny fraction of the biosynthetic pathways derived from (Z, )-famesyl pyrophosphate. Direct hydrolysis leads to acyclic sesquiterpenoids such as famesol (111) and nerolidol... 

When geranyl pyrophosphate reacts with isopentenyl pyrophosphate, the result is the 15-carbon famesyl pyrophosphate, which is an intermediate in the biosynthesis of sesquiterpenes such as famesene. Oxidation can then provide sesquiterpenoids such as famesol and juvenile hormone (Fig. 116.2). 

Many natural products are derived from 3-methyl-3-butenyl pyrophosphate, including the terpenes first discussed in Section 4-7. Indeed, the structures of terpenes can be dissected into five-carbon units connected as in 2-methyl-l,3-butadiene. Their structural diversity can be attributed to the multiple ways in which 3-methyl-3-butenyl pyrophosphate can couple. The monoterpene geraniol and the sesquiterpene famesol, two of the most widely distributed substances in the plant kingdom, form by hydrolysis of their corresponding pyrophosphates. 

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