Biosynthesis of terpenes

Strategy Problem 6 A labelled compound for biosynthetic studies. Mevaloitic acid (TM 418) is an intermediate in the biosynthesis of terpenes and steroids (Tedder, volume 4, p.217 ff). To study exactly what happens to each carbon atom during its transformation into, say, hmonene (418A), we need separate samples of mevalonic acid labelled with in each carbon atom in the molecule. This turns our normal strategy on its head since we must now look for one carbon discoimections. You can use reagents like Na CN, and... 

Ketene dimer (28), made from [ " Cl-labelled acetic acid, has been used to make doubly labelled mevalonic lactone (29) for studies on the biosynthesis of terpenes. Note... 

A recent example demonstrates that corals rely on induced biosynthesis of terpenes as a dynamic defense strategy as well. The induction of terpenoid secondary metabolites was observed in the sea whip Pseudopterogorgia elisabethae [162]. Levels of pseudopterosins 89-92, a group of diterpene glycosides with anti-inflammatory and analgesic properties (Scheme 23) [163-165], are increased in response predation by the mollusk Cyphoma gibbosum. First bioassays indicate that these natural products are involved in the chemical defense. 

Terpenes, biogenetically, arise from two simple five-carbon moieties. Isoprenyl-diphosphate (IPP) and dimethylallyldiphosphate (DMAPP) serve as universal precursors for the biosynthesis of terpenes. They are biosynthesised from three acetylcoenzyme A moieties through mevalonic acid (MVA) via the so-called mevalonate pathway. About 10 years ago, the existence of a second pathway leading to IPP and DMAPP was discovered involving l-deoxy-D-xylulose-5-phos-phate (DXP) and 2C-methyl-D-erythritol-4-phosphate (MEP). This so-called non-mevalonate or deoxyxylulose phosphate pathway starts off with the condensation of glyceraldehyde phosphate and pyruvate affording DXP. Through a series of reactions as shown in Fig. 4.1, IPP and DMAPP are formed, respectively [3,7, 42, 43]. 

In view of the importance of mevalonate in the biosynthesis of terpenes and steroids, it is not surprising that numerous syntheses of mevalonolactone are available. These are briefly itemized in the detailed procedure for the synthesis of (i ,S)-mevalonolactone labelled at C-2 with 13C (Scheme 215) (81OS(60)92>. 

The biosynthesis of terpenes clearly follows a somewhat different course from fatty acids in that branched-chain compounds are formed. One way that this can come about is for 2-oxobutanoyl coenzyme A to undergo an aldol addition at the keto carbonyl group with the ethanoyl coenzyme A to give the 3-methyl-3-hydroxypentanedioic acid derivative, 8 ... 

This chemical experiment aims to imitate the biosynthesis of terpenes. A mixture of products results. Draw a mechanism for the reaction. To what extent is it biomimetic, and what can the natural system do better ... 

Tada, M., and Lynen, F. (1961). On the biosynthesis of terpenes. XIV. On the determination of phosphomevalonic acid kinase and pyrophosphomevalonic acid decarboxylase in cell extracts. J Biochem 49 758-764. 

The coenzyme form of pantothenic acid is coenzyme A and is represented as CoASH. The thiol group acts as a carrier of acyl group. It is an important coenzyme involved in fatty acid oxidation, pyruvate oxidation and is also biosynthesis of terpenes. The epsilon amino group of lysine in carboxylase enzymes combines with the carboxyl carrier protein (BCCP or biocytin) and serve as an intermediate carrier of C02. Acetyl CoA pyruvate and propionyl carboxylayse require the participation of BCCP. The coenzyme form of folic acid is tetrahydro folic acid. It is associated with one carbon metabolism. The oxidised and reduced forms of lipoic acid function as coenzyme in pyruvate and a-ketoglutarate dehydrogenase complexes. The 5-deoxy adenosyl and methyl cobalamins function as coenzyme forms of vitamin B12. Methyl cobalamin is involved in the conversion of homocysteine to methionine. 

Degradation products of LOOHs are able to initiate the production of the ethylene, kinases and G-proteins required to induce an oxidative burst. These events are apparently followed by activation of the genes which encode the generation of jasmonic acid and of salicylic acid. These are in turn able to induce the production of enzymes of the phenylpropanoid pathway [149,150], and enzymes which initiate the biosynthesis of terpenes (e.g. 3-hydroxy-3-methylglutaryl coenzyme A reductase [145,151-153]) and lignins. 

It appears that the intermediate primary norbornadien-7-ylmethyl cation did not undergo ring enlargement leading to product arising from a secondary bicyclo[2.2.2]octa-2,5-dienyl cation but, more likely formation of a delocalized homoallyl cation through the double bonds of the norbornadiene system - is responsible for the formation of the tetracyclooctane derivative. Such homoallyl cations have been considered as intermediates in the biosynthesis of terpenes. 

The basic unit in the biosynthesis of terpenes is the isoprene molecule, isopren-fenylpyrophosphate formed from acetate in the mevalonic acid pathway, which can self-condense in various ways usually head to tail , less frequently, tail to tail or head to head . 

Willadsen and Eggerer (75) have studied the stereochemistry of the enzyme acetyl CoA acetyltransferase, a key enzyme in both the terminal step in C-3 oxidation of fatty acids and the initial step in the biosynthesis of terpenes and steroids. The enzyme, when incubated separately with (2S)-[2-2Hi,2-3Hi]aceto-acetyl CoA and the (2R) isomer gave two moles of acetyl CoA as depicted in Scheme 17. Eggerer et al. (76) utilized the enzyme enoyl CoA hydratase to convert properly labeled crotonyl CoA, via syn addition, to the doubly isotopically labeled 3-hydroxyacyl CoA derivatives needed in this study. A discussion of this unique type of hydration has been presented by Rose (9). The labeled... 

In Section 26.8, we will see that the compound actually used in the biosynthesis of terpenes is not isoprene, but isopentenyl pyrophosphate, a compound that has the same carbon skeleton as isoprene. We will also look at the mechanism by which isopentenyl pyrophosphate units are joined together in a head-to-tail fashion. 

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