Mevalonic acid lactone

There is some interesting new methodology that has been worked out in the course of these studies 73>76>. in general, stereospecificity relations of this sort are examined with the help of other enzyme reactions of known stereospecificity. When mevalonic acid (lactone form, 8 is fed to Claviceps, the 5-Hs atom is incorporated into the ergot alkaloids agroclavin 9a and elymoclavin 9b, whereas the 5Hr, atom is lost. 

Mevalonic acid lactone. Mevalonic acid 5-phosphate, Mevalonic acid 5-pyrophosphate... 

The biosynthesis of roquefortine was investigated by feeding labeled mevalonic acid lactone, tryptophan, and histidine to Penicillium roqueforti these compounds were incorporated (190,191). A biogenetic pathway for roquefortine obtained from Stilton cheese has been suggested (191). 

Kumar, B., Andreatta, C., Koustas, W.T., Cole, W.C., Edwards-Prasad, J., and Prasad, K.N. (2002). Mevastatin induces degeneration and decreases viability of cAMP-induced differentiated neuroblastoma cells in culture by inhibiting proteasome activity, and mevalonic acid lactone prevents these effects. JNeurosci Res 68 627-635. 

In the course of biosynthetic studies on the antibiotic, siccanin (46), Nozoe et al. have not only isolated trans-y-monocyclofarnesol (47) from the mycelia of the fungus, Helminthosporium siccans, but they have also demonstrated that a cell-free enzymatic preparation from the fungi converts mevalonic acid lactone into (47) in high yield. A key intermediate in the synthesis of abscisic acid is (48), which... 

This has been justified when radioactive tryptophan or tryptamine (decarboxytryptophan) were incorporated into several indole alkaloids ( 54-57).It has also been predicted that the non-tryptophan portions of these alkaloids are formed from two mevalonate units to afford a cyclopentane monoterpenoid precursor (58,59). This was proved upon feeding dl-[2- C]-mevalonic acid lactone, and sodium ( )-[2- C] mevalonate into vinca rosea plants and resulted in the isolation of radioactive vindoline, catharan-thine and ajmalicine ( 60-64). 

The biosynthesis starts from isochorismic acid, 2-oxoglutaric acid, and mevalonic acid lactone, see an-thranoids. 

Studies in which [2--mevalonic acid lactone ( mevalonate ) (105) was used as a precursor showed that three molecules were incorporated into trichothecolone (101), the label appearing at positions 4, 8, and 14 (249), The involvement of 2-rran5-6-rra -famesyldiphosphate (106) had been shown previously using " C-labelled material 250), The biosynthesis thus follows a standard sesquiterpene pathway from mevalonate through famesyldiphosphate to nerolidyldiphosphate (107) (257, 252), which is then cyclised by the enzyme trichodiene synthase to the bicy-clic hydrocarbon trichodiene (49) (253). The evidence for the participation of nerolidyldiphosphate has been reviewed (254, 255). None of the possible enzyme bound intermediates has been isolated from what is shown (107, 108) as a concerted process involving a 1,4-hydride shift and two 1,2-methyl shifts (256),... 

Scheme 2. Biosynthesis of trichodiene (49) and trichothecolone (101) from mevalonic acid lactone (105), labelled atom <...

J. MacMillan and C.M. Weis, Detailed analysis of metabolites from mevalonic acid lactone in Gibberella fujikuroi. Phytochemistry 13, 1413-7 (1974). 

Table 1. Incorporation of DL-[2- H]-mevalonic acid lactone into putative cytokinins by Datura innoxia crown-gall tissue with and without the enzyme inhibitor compacting...

Three-week-old tissue (2 g fw) was used. pH]-mevalonic acid lactone was added at the end of 4 h pre-incubation period. 

The first significant biosynthetic experiment conducted in this family was reported by Birch and Wright in 1970 [8] wherein dl-[3- C]-tryptophan, [2- C]-mevalonic acid lactone, Na[2- C]acetate, and l-[U- C]-proline were shown to be incorporated into hrevianamide A in significant amounts as shown in Table 1. It was also shown that [ CHj]-methionine was not incorporated into... 

Subsequently, Birch and associates reported the biosynthetic incorporation of doubly radiolabeled brevianamide F (cydo-L-tryptophyl-L-proline) into brevianamide A in Penicillium brevicompactum [13]. Thus, feeding experiments were conducted with DL-[met/zy/ene- C]-tryptophan, l-[5- H]-proline, dl-[2- C]-mevalonic acid lactone, and 9/c/o-L-[met/zy/ene- C]-tryptophyl-L-proline as shown by the resulting data in Table 2. The specific molar incorporations were determined by feeding precursors of certain specific activities and recrystallizing the brevianamide A produced under these conditions to constant activity without the addition of cold, unlabeled brevianamide A. 

In a particularly provocative study, Gorst-Allman et al. fed [ 1,2--labeled acetate and [2,3- C]-labeled mevalonic acid lactone to cultures of Penicillium roqueforti and Penicillium crustosum [45] The NMR spectrum of the roquefortine showed that both C(26) and C(27) were coupled to C(23) (Fig. 9). This interesting result mandates that, during the incorporation of dimethylallyl pyrophosphate, the methyl groups become quasi-equivalent. 

Echinulin is a triisoprenylated cyclic dipeptide isolated from Aspergillus amstelodami and Aspergillus echinulatus (Fig. 12) [52]. Birch et al. established that the biosynthetic precursors to echinulin are L-tryptophan, L-alanine, and mevalonic acid [53] by feeding radioactive precursors to Aspergillus amsteloda-mu In these experiments it was found that [1- C] sodium acetate, dl-[1- C]-alanine,DL-[l- C]-tryptophan, [2- C]-mevalonic acid lactone, and [1- C]-glycine were incorporated into echinulin with incorporation rates of 4.25 %, 0.12 %, 1.36%, 0.74%, and 0.84%, respectively (Scheme 31). 

C]-acetate di-[1- C] alanine cll-[1- C] tryptophan [2- C]-mevalonic acid lactone... 

It was observed that there was a single -shifted C signal for C-27 in the i C[ H] NMR spectrum this observation is inconsistent with a mechanism involving an sp -hybridized intermediate at C-29. This was further corroborated by an observed a-isotope shift in the C [ H, H] NMR spectrum of verruculogen obtained from feeding (3RS)-[6- H3, 6- C]mevalonic acid lactone (99 atom% C) containing C, H3-(55 mol%) and C, H2-labeled (45 mol%) species at... 

Table 7. Incorporation of labeled mevalonic acid lactones into a-cyclopiazonic acid [79] ...

Mevalonic acid lactone Ratio of mevalonate Ratio in... 

From this data it was concluded that the (3J )-isomer of mevalonic acid lactone is incorporated into a-cyclopiazonic acid with retention of the 4-pro-i -hydrogen atom. 

DolichotheUne is an amide derivative from histamine of Dolichothele sphaerica (Cactaceae) whose structure suggests the cOTidensatiOTi of the imidazole unit with isovaleric acid [14, 15]. Its biosynthesis was evaluated by means of radiolabeled tracers such as DL-[2- " C]histidine, DL-[2- " C]leucine, DL-[2- " C]mevalonic acid lactone, and sodiiun [l- " C]isovalerate [42]. The extension of radioactivity... 

---