Mevalonic structure

Trace each of the carbon atoms of mevalonate through the synthesis of cholesterol, and determine the source (i.e., the position in the mevalonate structure) of each carbon in the final structure. 

A synthesis of the important biosynthetic intermediate mevalonic acid starts with the enzymatic hydrolysis of the diester A by pig liver esterase. The pro-R group is selectively hydrolyzed. Draw a three-dimensional structure of the product. 

The structures of (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 

The terpenoid precursor isopentenyl diphosphate, formerly called isopentenyl pyrophosphate and abbreviated IPP, is biosynthesized by two different pathways depending on the organism and the structure of the final product. In animals and higher plants, sesquiterpenoids and triterpenoids arise primarily from the mevalonate pathway, whereas monoterpenoids, diterpenoids, and tetraterpenoids are biosynthesized by the 1-deoxyxylulose 5-phosphate (DXP) pathway. In bacteria,... 

Eicosanoids and terpenoids are still other classes of lipids. Eicosanoids, of which prostaglandins are the most abundant kind, are derived biosynthetically from arachidonic acid, are found in all body tissues, and have a wide range of physiological activity. Terpenoids are often isolated from the essential oils of plants, have an immense diversity of structure, and are produced biosynthetically from the five-carbon precursor isopentenyl diphosphate (IPP). lsopentenyl diphosphate is itself biosynthesized from 3 equivalents of acetate in the mevalonate pathway. 

A considerable number of mycotoxins that show high toxicity to vertebrates and/ or invertebrates are produced by organisms associated with crop plants (Flannigan 1991). There are many known cases of human poisoning caused by such compounds. There are three broad categories of mycotoxins represented here, based on the structures of the intermediates from which these secondary metabolites are derived. They are (1) compounds derived from polyketides, (2) terpenes derived from mevalonic acid, and (3) cyclic peptides and derivatives thereof. 

More than half of the reported secondary metabolites from macroalgae are isoprenoids. Terpenes, steroids, carotenoids, prenylated quinines, and hydroqui-nones make up the isoprenoid class, which is understood to derive from either the classical mevalonate pathway, or the mevalonate-independent pathway (Stratmann et al. 1992). Melavonic acid (MVA) (Fig. 1.2) is the first committed metabolite of the terpene pathway. Dimethylallyl (dl meth al lal) pyrophosphate (DMAPP) (Fig. 1.3) and its isomer isopentenyl pyrophosphate (IPP, Fig. 1.3) are intermediates of the MVA pathway and exist in nearly all life forms (Humphrey and Beale 2006). Geranyl (ja ran al) (C10) and famesyl (C15) units are generated by head-to-tail (Fig. 1.3) condensation of two (for C10) or three (for C15) 5-carbon DMA-like isoprene units, identifiable in final products by the characteristic fish-tail repeating units, as traced over the structure of a sesquiterpene in Fig. 1.3 (Humphrey and Beale 2006). Additional IPP condensation with famesyl pyrophosphate (FPP)... 

Clicking on the product of the reaction, mevalonate, other related information such as 3-D structure with Ruby (Rule-based invention of conformations), a connection to TCM, WDI and WOMBAT are found. TCM depicts several similar compounds, one of which is citric acid with a 0.87 similarity to mevalonate. Clicking on it brings a list of 12 TCM sources in which citric acid appears (Figure 10.7 [52]). AH the sources come... 

Biological activities of structures similar to mevalonate can be found in WOMBAT. The closest similar molecule is in series 1062, which is (according to the paper it was published in) a novel thiol-containing citric acid analog (Figure 10.8 [53]). It has a measured Ki value that can be compared to other molecules in the series. The figure in bold indicates the common pattern for the majority of compounds in this series. 

Inhibition of HMG-CoA reductase. Top The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas). 

HGURE 21-45 Inhibitors of HMG-CoA reductase. A comparison of the structures of mevalonate and four pharmaceutical compounds that inhibit HMG-CoA reductase. 

The phosphorylation of mevalonate and presence of pyrophosphate in subsequent structures help keep these water-insoluble compounds in solution. 

Phytoene (Fig. 22-5) is apparently formed from geranylgeranyl-PP via prephytoene-Pf whose structure is entirely analogous to that of presqualene-pp 44,117 However, no reduction by NADH is required (Eq. 22-8). It is known that the 5-pro-R hydrogen atoms of mevalonate are retained in the phytoene as indicated by a shaded box in Eq. 22-8. Elimination of the other (pro-S) hydrogen yields 15,15 -Z phytoene (a s-phytoene), while elimination of the pro-R hydrogen yields all-E (trans) phytoene. Higher plants and fungi form mostly a s-phytoene, but some bacteria produce the all-E isomer.118... 

Figure 22-5 Structures and partial biosynthetic pathways for a few of the more than 600 known carotenoid compounds. The origin of some hydrogen atoms from mevalonate is shown, using the numbering for mevalonate. The numbering system for C40 carotenoids is also indicated.

Compound MC-033 (205), structurally similar to chlorothricin, has been isolated from a cultured broth of Streptomyces sp., and inhibits the biosynthesis of cholesterol from mevalonate with an IC50 value of 1.05 x 10° M [163]. 

Isoprenoid structures for carotenoids, phytol, and other terpenes start biosynthetically from acetyl coenzyme A (89) with successive additions giving mevalonate, isopentyl pyrophosphate, geranyl pyrophosphate, farnesyl pyrophosphate (from which squalene and steroids arise), with further build-up to geranyl geranyl pyrophosphate, ultimately to a- and /3-carotenes, lutein, and violaxanthin and related compounds. Aromatic hydrocarbon nuclei are biosynthesized in many instances by the shikimic acid pathway (90). More complex polycyclic aromatic compounds are synthesized by other pathways in which naphthalene dimerization is an important step (91). 

Structure of lovastatin acid, a potent competitive inhibitor of HMG-CoA reductase. Note the similarity in structure of the red portion of the molecule with mevalonate, the product of the HMG-CoA reductase reaction. 

Although sterols like cholesterol are not synthesized de novo by parasitic flatworms, they do possess an active mevalonate pathway (Fig. 20.3) (reviewed in Coppens and Courtoy, 1996). This pathway has been studied in 5. mansoni, and all available evidence indicates that it is similar to the lipid metabolism seen in F. hepatica. The mevalonate pathway was shown to be used by 5. mansoni for the synthesis of dolichols for protein glycosylation, of quinones as electron transporters in the respiratory chain and of farnesyl and geranylgeranyl pyrophosphates as substrates for the isopreny-lation of proteins (Chen and Bennett, 1993 Foster et a/., 1993). A key enzyme in the mevalonate pathway is 3-hydroxymethylglutaryl-CoA reductase (HMG-CoA reductase) and it was shown that the schistosomal enzyme differs from the mammalian type, both structurally and in its regulatory properties (Rajkovic et ai, 1989 Chen et at., 1991). Farnesyl pyrophosphate plays a key role in the mevalonate pathway as it is the last common substrate for the synthesis of all end products (Fig. 20.3). As mentioned already, the branch leading from farnesyl pyrophosphate via squalene to cholesterol is not operative in parasitic flatworms, whereas the other branches are active, at least in S. mansoni and probably also in F. hepatica and FI. diminuta. 

P. F. Wareing and his dormin group had, meanwhile, joined with Cornforth s team in the Shell Research Laboratories and they too succeeded in isolating the active compound for dormancy in shoots of sycamore (Cornforth et al., 1965). It had the same structure as Addicott s abscisin II Confirmation that both groups had isolated the identical substance came in the same year with Cornforth, Milborrow and Ryback s (1965) chemical synthesis of abscisin II. It was a sesquiterpene, the stereoisomer (S)-conformation being native (Figure 2e). Two pathways of synthesis seemed operative, de novo via mevalonate and the isoprene route, or as a degradation product of carotenoids. 

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