2-£-6-£-famesyl pyrophosphate

Introduction of Nitrogen into a Terpenoid Skeleton. The acetate-derived fragments (35) mevalonic acid (30), which yields isopentenyl pyrophosphate (31) and its isomer, 3,3-dimethyl ally pyrophosphate (32) a dimeric C -fragment, geranyl pyrophosphate (33), which gives rise to the iridoid loganin (34) and the trimer famesyl pyrophosphate (35), which is also considered the precursor to C q steroids, have already been mentioned (see Table 3... 

The trimer famesyl pyrophosphate (35), in addition to serving as a pregenitor of steroids via squalene (114), is also the pregenitor of the compounds known as sesquiterpenes. It has been suggested that famesyl pyrophosphate (88) similarly serves as the carbon backbone of alkaloids such as deoxynuphatidine (120) ftom Nupharjapomcum (Nymphaceae) (water hhes) and dendrobine (121) Dendrobium nobikl indl. (Orchidaceae) (Table 11). 

The latter is the source of the Chinese dmg Chin-Shih-Hu. Compared to the other families of bases discussed eadier, the numbers of alkaloids supposedly derived from famesyl pyrophosphate or a close relative is small. However, given the wide variety of plant families containing sesquiterpenes, it is most likely that the numbers of compounds to be found will dramatically increase. 

Whereas dimerization of two famesyl pyrophosphates (35) generates squalene (114) on the path to steroids (89), the addition of one more C unit, as isopentenyl pyrophosphate (31) or its isomer, 3,3-dimethyl ally pyrophosphate (32), to the C compound famesyl pyrophosphate produces the C2Q diterpene precursor geranylgeranyl pyrophosphate [6699-20-3] (122). 

The seminal publication [ 12] on the isolation of retigeranic acid proposed a possible biosynthetic pathway by means of cyclization from geranyl famesyl pyrophosphate (12) (Fig. 10.2) to tertiary carbocationic cyclopentane 13. A series of [1, 5] and [1, 2] hydride shifts were proposed to establish the skeletal core of the sesterterpene, whose subsequent oxidation would yield retigeranic acid. 

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

Earlier work by Nancy Bucher showed an ATP requirement for cholesterol biosynthesis. The involvement of phosphorylated intermediates was established by Comforth, Popjak, and their associates in the early 1960s with the discovery of kinases which successively phosphorylated MVA to MVA-P and MVA-P to MVA-PP. MVA-PP was decar-boxylated and dehydrated to give the biological C5 isoprene unit, isopentenyl pyrophosphate. This undergoes successive head-to-tail condensations to give the linear 15C terpenoid, famesyl pyrophosphate. 

Addition of Isoprenyl Groups A number of eukaryotic proteins are modified by the addition of groups derived from isoprene (isoprenyl groups). A thioether bond is formed between the isoprenyl group and a Cys residue of the protein (see Fig. 11-14). The isoprenyl groups are derived from pyrophosphorylated intermediates of the cholesterol biosynthetic pathway (see Fig. 21-33), such as famesyl pyrophosphate (Fig. 27-30). Proteins modified in this way include the Ras proteins, products of the ras oncogenes and proto-oncogenes, and G proteins (both discussed in Chapter 12), and lamins, pro-... 

Formation of squalene from famesyl pyrophosphate. Farnesyl transferase is tightly complexed to the endoplasmic reticulum. Three carbons are labeled . A, ) in different structures for purposes of tracking them as the reaction proceeds. 

Isopentenyl pyrophosphate acts as an alkylating agent toward famesyl pyrophosphate. Alkylation is followed by loss of a proton from the carbocation intermediate, giving geranylgeranyl pyrophosphate. Hydrolysis of the pyrophosphate yields geranylgeraniol. 

The first recognizable steroid ring system is lanosterol it is formed first by the epoxidation of the double bond of squalene that was originally derived from a DMAPP through famesyl pyrophosphate, and... 

Sesquiterpenes have 15 carbons. The parent for this family is famesyl pyrophosphate, which is produced by the addition of the carbocation derived from geranyl pyrophosphate to isopentenyl pyrophosphate. This reaction is very similar to the formation of geranyl pyrophosphate shown in Figure 28.2. 

Show a mechanism for the formation of these compounds from famesyl pyrophosphate ... 

Glickman, J.F. and A. Schmid. 2007. Famesyl pyrophosphate synthase real-time kinetics and inhibition by nitrogen-containing bisphosphonates in a scintillation assay. Assay Drug Dev. Technol. 5, 205-214. 

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