Mevalonic Mevalonolactone

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>. 

Jeffrey pine beetle, Dendroctonus jeffreyi Hopkins, which had been previously treated with juvenile hormone III (JH III, 2.2 pg/beetle in acetone) and then placed in an aeration tube for 25 to 30 h. Ips paraconfusus and I. pini were each injected with 0.2 pCi of sodium [1-14C]acetate prior to placement in cut pine logs and volatile collection, while D. jeffreyi were each injected with 3.8 (male) and 3.7 (female) pCi of sodium [1-14C]acetate 6.4 (male) and 10.7 (female) h after JH application. (G) The role of the mevalonate pathway in frontalin biosynthesis is supported by the incorporation of radiolabel from [2-14C]mevalonolactone into frontalin by male D. jeffreyi (2.2 pg JH 11 l/beetle in acetone, 10 h incubation and volatile collection, 1.1 pCi of [2 14C] mevalonolactone injected, 20 h volatile collection). Figures adapted from Seybold et al. (1995b) and Barkawi (2002). 

Methyl vinyl ketone, 31-32, 225, 676, 697-703, 887, 970, 974,1112 Methyl a- and /5-xylopyranoside, 834 DL-Mevalonic acid 5-phosphate, 811 Mevalonolactone, 146, 809-810 (R and S), 809 Michael reaction, 1069 Mitomycin, 941 Mobay, 1171 Molecular rotations, 297 Molecular sieves, 333, 431, 703-705, 739 Mondur TD-80,1171 Monobromopentaerythritol, 450 Monochlorourea, 1107,1267 Monoethylamme-borane, 16 Monoethyl raalonate, 523 Monomethylamine-borane, 16 Monoperoxytucdnic acid, an Penuodnlc acid... 

Fig. 5. Analogs that inhibit HMG-CoA reductase. A, mevalonic acid B, compactin C, mevinolin D, mevalonolactone derivatives.

Mevalonolactone was used instead of the anion, mevalonate, because only the former is permeable to mammalian cells. 

The identity of the multiple signals which regulate HMG-CoA reductase levels has yet to be established. One of these appears to be a sterol or sterol derivative. The second appears to be mevalonate or one of its metabolites [141]. Leading candidates for the sterol signal(s) are oxygenated derivatives of cholesterol. These are present in the circulation and many are potent suppressors of HMG-CoA reductase levels [175-177]. A candidate for the regulatory metabolite of mevalonate is isopentenyl adenine. Compactin added to baby hamster kidney-21 cells completely inhibits both DNA synthesis and cell proliferation [178]. Added mevalonolactone relieved this inhibition, but added sterols did not. Isopentenyl adenine also relieved compactin inhibition, and did so 100-200 times more effectively than did mevalonolactone [178]. 

Scheme 11.40. A representation of the reduction of (35 )-3-hydroxy-3-methylglutaryl CoA to (R)-mevalonic acid [(R)-3,5-dihydroxy-3-methylpentanoic acid] by the enzyme hydroxymethylglutaryl-CoA reductase (EC 1.1.1.34). The corresponding lactone mevalonolactone is also shown.

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. 

Figure 6.5 The key compounds mevalonic acid and its lactone, with fluoro-mevalonolactone, an inhibitor of the terpene pathway...

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