O O

„ , t f H20 + C02 + f NX ^ p p h+ hac^x ^o^" po" toh isopentenyl pyrophosphate IPP

dimethallyl pyrophosphate DMAPP

Figure 6.2 The early stages in terpene biosynthesis to give the two building blocks, IPP

and DMAPP Here the diphosphate or pyrophosphate groups are shown in full, in subsequent figures they are represented by OPOP

terpenes. Mevalonic acid is converted to the pyrophosphate (also called diphosphate) and then decarboxylated with simultaneous loss of hydroxyl, to give isopentenyl pyrophosphate (IPP). Three enzymes are required here. IPP is the basic building block of the terpene series, but one more reaction, on an isomerase enzyme, is required to make dimeth-allyl pyrophosphate (DMAPP), the starting unit for terpenes. Note that labelling experiments with deuterium and tritium have shown that it is the pro-chiral HR of IPP (from the back of the molecule as drawn) that is removed in this step.

The combination of isopentenyl pyrophosphate (IPP) and dimethallyl pyrophosphate (DMAPP) on prenyl transferase gives geranyl pyrophosphate, the parent of all the monoterpenes. The IPP is added from above to the DMAPP as phosphate is eliminated from below, so this centre is inverted. The pro-chiral HR on IPP is eliminated from the resulting carbocation (Figure 6.3).

DMAPP geranyl pyrophosphate

Figure 6.3 The condensation of IPP and DMAPP to give geranyl pyrophosphate. The prochiral hydrogens are here labelled A, B, C and D because they change their chiral labels during the reaction

DMAPP geranyl pyrophosphate

Figure 6.3 The condensation of IPP and DMAPP to give geranyl pyrophosphate. The prochiral hydrogens are here labelled A, B, C and D because they change their chiral labels during the reaction

Hydrolysis of the pyrophosphate with pyrophosphatase gives geraniol (Figure 6.4) directly. Cleavage of the carbon-oxygen bond gives a carbocation and pyrophosphate ion. The carbocation can undergo various changes to provide a number of monoterpene compounds (Figure 6.4).

Mevalonic acid, the key intermediate in solving the terpene biosynthesis pathway is an oily liquid, in solution it is in equilibrium with mevalonolactone (Figure 6.5), a crystalline solid, so the latter is used in biosynthetic studies. Fluoromevalonolactone, and the corresponding acid, are powerful inhibitors of terpene formation. If addition of fluoromevalonate to a biosynthesizing system blocks the formation of a compound, then it can be concluded that that compound has a terpene origin.

6.1.1 The Methylerythritol Phosphate Pathway

It was discovered in 1995 by M. Rohmer that micro-organisms, green algae and plastids (membrane-bound organelles of plants, e.g. chloroplasts)

borneol

Figure 6.4 The derivation of some simple monoterpenes from geranyl pyrophosphate borneol

Figure 6.4 The derivation of some simple monoterpenes from geranyl pyrophosphate hcl £h3 hcl xch3 ho ch2f oh +h20 0 ^0

mevalonic acid mevalonolactone 6-fluoromevalonolactone

Figure 6.5 The key compounds mevalonic acid and its lactone, with fluoro-mevalonolactone, an inhibitor of the terpene pathway use a different pathway to mevalonic acid, as outlined in Figure 6.6. It is not surprising that in plants, where sugars are abundant, the starting materials are sugar derivatives. The process begins with pyruvic acid being decarboxylated using thiamine diphosphate (Chapter 2) and the intermediate being condensed with glyceraldehyde 3-phosphate (GAP) (Figure 2.20) to give 1-deoxy-d-xylulose 5-phosphate (DXP). This undergoes rearrangement and reduction to methylerythritol 4-phosphate. Details of the steps between methylerythritol 4-phosphate and isopente-nyl phosphate have not yet been studied in detail. The discovery of a new route to terpenes so long after the original elucidation of their formation from acetate and malonate was a great surprise, and has altered our concept of plant terpene production. Incidentally, DXP is also an intermediate in the synthesis of both thiamine and pyridoxal (Chapter 2).

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