Activated isoprene units

Synthesis takes place in four stages, as shown in Figure 21-33 (D condensation of three acetate units to form a six-carbon intermediate, mevalonate (2) conversion of mevalonate to activated isoprene units (3) polymerization of six 5-carbon isoprene units to form the 30-carbon linear squalene and ( ) cyclization of squalene to form the four rings of the steroid nucleus, with a further series of changes (oxidations, removal or migration of methyl groups) to produce cholesterol. 

FIGURE 21-35 Conversion of mevalonate to activated isoprene units. Six of these activated units combine to form squalene (see Fig. 21-36). The leaving groups of 3-phospho-5-pyrophosphomevalonate are shaded pink. The bracketed intermediate is hypothetical. 

Stage (J) Condensation of Six Activated Isoprene Units to Form Squalene Isopentenyl pyrophosphate and dimethylallyl pyrophosphate now undergo a head-to-tail condensation, in which one pyrophosphate group is displaced and a 10-carbon chain, geranyl pyrophosphate, is formed (Fig. 21-36). (The head is the end to which pyrophosphate is joined.) Geranyl pyrophosphate undergoes another head-to-tail condensation with isopentenyl pyro-... 

The biosynthesis of monoterpenoids and camphor has been described by several authors (108-llU). Ruzicka (115,116) proposed a unified biogenetic scheme for terpenes. The biosynthetic building blocks for these terpenes are iso-prene units. The biosynthetically active isoprene units are isopentenyl pyrophosphate [l] and dimethyl allyl pyrophosphate [2] the compounds that are derived from acetate via mevalonic acid (Scheme V). Geranyl pyrophosphate [3] is the C-10 precursor for the terpenes (117). Banthorpe and Baxendale (ll8) confirmed the biosynthetic pathway of (iamphor via acetate mevalonate by conducting degradation study of camphor, biosynthesized from l c labelled mevalonic acid. The biosynthesis of camphor is summarised in Scheme VI. 

Stage one is the synthesis of isopentenyl pyrophosphate, an activated isoprene unit that is the key building block of cholesterol. 

Mevalonate is converted into 3-isopentenylpyrophosphate in three consecutive reactions requiring ATP (Figure 26.8). Decarboxylation yields isopentenyl pyrophosphate, an activated isoprene unit that is a key building block for many important biomolecules throughout the kingdoms of life. We will return to a discussion of this molecule later in the chapter. 

Fig. 34.5. The formation of activated isoprene units (A -isopentenyl pyrophosphate and dimethylallyl pyrophosphate) from mevalonic acid. Note the large ATP requirement for these steps.

E) Condensation of six activated isoprene units to form squalene... 

Although, terpenoids show enormous chemical and structural diversity, their backbones are synthesized from only two universal precursors isopentenyl pyrophosphate (IPP) and its highly electrophilic allyUc isomer dimethylaUyl pyrophosphate (DMAPP) [25]. IPP is isomerized to DMAPP by the enzyme isopentenyl pyrophosphate isomerase. The mevalonate pathway for the biosynthesis of terpenoids has been illustrated in Fig. 86.3. To summarize, the active isoprene unit (IPP) is repetitively added to DMAPP or a prenyl diphosphate in sequential head-to-tail... 

Diterpenes are formed by head (isopropylidene end) to tail (alcohol end) of four isoprene (CsHg) building blocks. The isoprene unit itself originates by the decomposition of natural cyclic hydrocarbons giving rise to the biochemically active isoprene units, identified as the pyrophosphate esters dimethylallyl diphosphate (DMAPP) and isopentenyl diphosphate (IPP) (Scheme 102.1). 

Biosynthetically, all terpenoids are traced back to a common synthon of biochemically active isoprene unit found in the forms of pyrophosphate esters either as dimeth-ylallyl diphosphate (DMAPP) or isopentenyl diphosphate (IPP) (Fig. 5.1). In turn, DMAPP and IPP are derived by two distinct biosynthetic pathways, the mevalonate pathway (MVA pathway) and the mevalonate-independent pathway or pathway of deoxyxylulose phosphate (DXP pathway), which are considered to be the major natural synthetic routes for the synthesis of terpenoids (Fig. 5.2). 

The biosynthetic pathways leading to the formation of (mono)terpenes by different organisms have been systematically investigated in the past [1 ]. As already discussed in the preceding chapter, the biosynthesis sequence conunences with formation of the two key building blocks isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2) either via the mevalonate or the mevalonate-independent pathway [1, 3, 4]. These two compounds represent the activated isoprene units that can be assembled and... 

Besides classical monoterpenes that are formed via a head-to-tail addition of IPP to DMAPP (and the analogous addition of IPP to advanced intermediates toward higher terpenes), there are also monoterpenes known where the CIO skeleton cannot be rationalized by this standard coupling of the two activated isoprene units. Two important examples are chrysanthemic acid (60) and pyrethric acid (61), which are the main (ester bound) building blocks for the well-known family of the pyrethrins [1, 13]. In this case, an enzyme-catalyzed... 

Sesquiterpenes are a major class of terpenes consisting of three isoprene units, providing the formula of to then-molecular structures (Fig. 7.1) [1]. Like all terpenes, their carbon skeletons are derived from the sequential addition of the active isoprene unit isopentenyl diphosphate (IDP or IPP) to other active diphosphates. In the case of sesquiterpenes, addition of a further IDP unit to geranyl diphosphate (GDP or GPP) (the essential precursor of all monoterpenes, please see Chapter 6) provides the fundamental sesquiterpene precursor famesyl diphosphate (FDP or FPP). 

Isopentenyl Pyrophosphate, the Active Isoprene Unit." Mevalonic acid is subjected to several changes before it can condense to form larger compounds. First it is phosphorylated, the pyrophosphate being formed with the consumption of 2 ATP, In a complex reaction, whose detailed mechanism is not understood, H2O and CO2... 

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