Mevalonate derivatives

Nakanishi, M., Goldstein, J.L., and Brown, M.S. (1988). Multivalent control of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Mevalonate-derived product inhibits translation of mRNA and accelerates degradation of enzyme. J Biol Chem 263 8929-8937. 

HMG-CoA reductase is also subject to translational control by a mevalonate-derived non-sterol regulator (D. Peffley, 1985 M. Nakanishi, 1988). Tliis component of the regulatory mechanism can be observed only when cultured cells are acutely incubated with statins, which block mevalonate formation. Under those conditions, sterols have no effect on HMG-CoA reductase mRNA translation however, mevalonate reduces the HMG-CoA mRNA translation by 80% with no change in mRNA levels. Translational control of hepatic HMG-CoA reductase by dietary cholesterol was shown in an animal model in which polysome-associated HMG-CoA reductase mRNA was analyzed in cholesterol-fed rats (C.M. Chambers, 1997). It was found that cholesterol feeding increased the portion of mRNA associated with translationally inactive monosomes and decreased the portion of mRNA associated with translationally active polysomes. The mechanism of HMG-CoA reductase translational control has not been elucidated. 

Biogenetic synthesis of the aspidospermine skeleton requires the preparation of an intermediate with the skeleton of the Cio mevalonate-derived unit from which the aliphatic carbon skeleton of rings C and D is built and its subsequent condensation with tryptamine. Such a... 

Echinulin.— The mould metabolite echinulin (126) and its relatives have been the subject of some elegant biosynthetic experiments leading to a clear picture of the way they are elaborated." Echinulin has recently been used as a monitor for the stereochemistry involved in the catabolism of leucine to mevalonic acid " label from the leucine was expected at specific sites in the mevalonate-derived iso-prenoid units of (126). In the event, extensive scrambling of label was observed from the two enantiomers of leucine chirally labelled with "C at C-3. Some selectivity in the labelling was detected, which was interpreted as indicating that carriage of label from leucine to mevalonate had occurred via acetoacetate. 

The six-carbon moiety attached to C-15 in verrol and the trichoverrins is mevalonate-derived 248), and after cyclisation to form the macrolide, the 2 -ene can undergo hydrogenation, a-epoxidation, or hydration. The ethylenic double bonds in the acetate-polymalonate-derived eight-carbon moiety attached to C-4 in the trichoverroids occur as Z or E (see Table 1), but are always 7 (E), 9 (Z) in the macrolide. 

Kolkmann and Leistner, 1987 Leistner, 1986). The final steps of formation of vitamin K2 (35) involve the addition of a mevalonate-derived unit (Fig. 6.7) (see Chapter 18), and methylation. 

Anthraquinones in which only one ring is substituted are particularly common in the Bignoniaceae, Rubiaceae, and Verbenaceae, but do not appear to occur in fungi, the Poly-gonaceae, Rhamnaceae, Fabaceae, Caesalpinioideae, or the Liliaceae (A/oe). These compounds are derived from a pathway similar to that previously discussed for naphthoquinones, but with subsequent addition of mevalonate-derived units (Fig. 6.8). 

In addition to relatively simple coumarins, a second group of more complex coumarins is known in which the coumarin structure is prenylated (i.e., a five-carbon unit derived from mevalonic acid metabolism is attached). The five-carbon mevalonate-derived unit of these compounds usually is re-... 

Many alkaloids contain an indole nucleus as a part of their structure. Monoterpene-derived indole alkaloids see Chapter 34) are the most important of these compounds, but several other significant types of indole alkaloids exist. Ergot alkaloids formed from tryptamine and a mevalonate-derived hemiterpene unit are of medical importance. Others, such as harmane alkaloids, physostigmine and a series of structurally similar alkaloids, Calycanthus alkaloids (Calycanthaceae) and related compounds (principally from the Rubiaceae), and relatively minor types of alkaloids from the Ascelpiada-... 

Many groups of alkaloids possess five-carbon mevalonate-derived units as a part of the overall structure of the compounds. In one previously discussed group, the ergot alkaloids, this mevalonate unit is attached to a tryptophan-derived portion and cyclized to form tricyclic and tetracyclic alkaloids. 

Information on the origin of angular furanocoumarins has not been plentiful, but much more is known about the more widely distributed linear isomers. In brief, the committed step in the pathway is the condensation of mevalonate-derived dimethylallyl pyrophosphate (DMAPP) at position 6 of umbelliferone to yield 7-dimethylsuberosin (Scheme 5). A transferase mediating this step was identified and characterized in Ruta graveolens 3 o 3 d evidence was obtained that it is a chloroplast enzyme.Cyclization... 

Elson CE, Yu SG (2004) The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. J Nutr 124 607-614... 

There has been much interest in the biosynthesis of coumarins bearing isoprenoid-related substituents these are now considered to be mevalonate derived 338, 340, 341). In part this has stemmed from the important skin-sensitizing activity of some furanocoumarins which has been correlated with their photoreactivity towards pyrimidine bases of DNA 409). The proposal by Birch (72) that the two extra carbon atoms of the furan ring are derived by loss of three carbon atoms from an intermediate hydroxyisopropyldihydrofuranocoumarin has received considerable experimental support in recent years 152, 198, 199). Indeed, it has now been established that ( + )-marmesin (103), formed from umbelliferone (2) via 7-demethylsuberosin (86) is a key intermediate in the biosynthesis of linear furanocoumarins 105, 107,... 

Compounds derived biogenetically from mevalonic acid are considered as mevalonate derivatives. In the lichens these comprise diterpenes, triter-penes, steroids, and carotinoids. 

The full details of sesquiterpene biosynthesis in chamomile are not yet known. Isolation of the prenyltransferase(s) responsible for the final steps in the biosynthesis and identification of the site of biosynthesis are likely to shed further light on the conundrum of biosynthetic compartmentation in flowering plants. These studies may also offer a challenge to the accepted wisdom that sesquiterpene biosynthesis in other flowering plants is always simply a matter of the processing of mevalonate-derived FPP in the cytosol. 

Deneris ES, Stein RA, Mead JF. Acid-catalyzed formation of isoprene from a mevalonate-derived product using a rat liver cytosolic fraction. J Biol Chem, 1985 260 1382-1385. 

A pronounced trend towards diversification of mevalonate derived metabolites (mono, sesqui, di and triterpenoids). 

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