Mevalonic acid chemical structure

Pravastatin and simvastatin are chemically modified derivatives of lovastatin. Atorvastatin, fluvastatin, and rosuvastatin are structurally distinct synthetic compounds. Statins exert their major effect—reduction of LDL levels—through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit... 

The incorporation experiments by Birch and co-workers (33,34), using [2- C]mevalonic acid, L-[l- 4C]alanine, and L-tryptophan, provided valuable information for the structural elucidation. Echinulin possesses two asymmetric centers, l-Alanine is obtained by acid hydrolysis, but another chiral center on the tryptophan moiety is easily racemized. Later, it was determined as the l form by microbioassay of the aspartic acid obtained by ozonolysis (35). Finally, the chemical structure 12 was confirmed by the stereoselective total synthesis of optically active echinulin by Kishi and co-workers (36) (Scheme 5). 

On the chemical side it has long been the practice of the chemist to attempt to discern common denominators within a class of natural products by a process which can best be regarded as a visual dissection of the structural formulae. The most well-known example of such an exercise has been the recognition of repeating branched chain five carbon units in terpenes and the subsequent use of this observation in reverse in order to frame structures which could then be tested against the experimental results. Mevalonic acid has turned out to be the biochemical equivalent of the hypothetical branched five carbon unit. In the case of indole alkaloids not quite so much progress has been made. 

The identity of C(8) of trichothecenes with C(2) of mevalonate was also proven directly, i.e., without the necessity of troublesome degradations and chemical conversions, by using [ Cjmevalonate (Hanson et ai, 1974). The only centers showing any enrichment in the C-NMR spectrum after the incorporation of [2- C]mevalonic acid into trichothecolone (25) were C(4), C(8), and C(14). That C(8)—and not C(10), as reported by Jones and Lowe (1960)—is derived from C(2) of mevalonate gives rise to the suggestion that the farnesyl pyrophosphate precursor of the trichothecenes is coiled as shown in structure 56, not as in structure 57 (Fig. 10) (Achilladelis et ai, 1970, 1972). 

The wide distribution of PKSs in the microbial world and the extreme chemical diversity of their products do in fact result from a varied use of the well-known catalytic domains described above for the canonical PKS systems. Taking a theoretic view of polyketide diversity, Gonzalez-Lergier et al. (41) have suggested that even if the starter and extender units are fixed, over 100,000 linear heptaketide structures are possible using only the 5 common reductive outcomes at the P-carbon position (ketone, (R- or S-) alcohol, trans-double bond, or alkane). Recently, it has become apparent that even this does not represent the upper limit for polyketide diversification. To create chemical functionalities beyond those mentioned above, nature has recruited some enzymes from sources other than fatty acid synthesis (the mevalonate pathway in primary metabolism is one example) not typically thought of as type I PKS domains. Next, we explore the ways PKS-containing systems have modified these domains for the catalysis of some unique chemistries observed in natural products. 

Cholesterol is primarily restricted to eukaryotic cells where it plays a number of roles. Undoubtedly, the most primitive function is as a structural component of membranes. Its metabolism to bile acids and the steroid hormones is relatively recent in the evolutionary sense. In this chapter, the pathway of cholesterol biosynthesis will be divided into segments which correspond to the chemical and biochemical divisions of this biosynthetic route. The initial part of the pathway is the 3-step conversion of acetyl-CoA to 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). The next is the reduction of this molecule to mevalonate, considered to be the rate-controlling step in the biosynthesis of polyisoprenoids. From thence, a series of phosphorylation reactions both activate and decarboxylate mevalonate to isopen tenyl pyrophosphate, the true isoprenoid precursor. After a rearrangement to the allylic pyrophosphate, dimethylallyl pyrophosphate, a sequence of l -4 con-... 

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