Mevalonate sterol precursor

Atorvastatin is a selective, competitive inhibitor of the 3-hydroxy methyl glutaryl coenzyme A (HMG-CoA) reductase enzyme that is involved in the conversion of HMG-CoA to mevalonate (a precursor of sterols, including cholesterol). A reduction of intracellular cholesterol levels... 

U. tomentosa is a significant traditional medicinal plant that is an important source of monoterpenoid oxindole alkaloids (MOAs) with bioactivities including immunomodulatory, cytotoxic, anti-HIV, and antileukemic activities [100]. It will be of interest to understand biosynthetic insights of bioactive compounds of this plant as an example here. Studies have reported the regulation of biosynthesis of sterols and triterpenes in U. tomentosa [100]. Administration of pectin to U. tomentosa cell suspension cultures increased the activity of isopentyl diphosphate isomerase of ursolic and oleanolic acid. The treated cells also transformed a higher percentage of labeled mevalonic acid precursors into triterpenes and resulted in the decrease in activity of far-nesyl diphosphatase by a factor of two when compared to the control. The... 

Since carotenoids are isoprenoids, they share a common early pathway with other biologically important isoprenoids such as sterols, gibberellins, phytol and the terpenoid quinones (Fig. 13.3). In all cases, these compounds are derived from the C5 isoprenoid, isopentenyl diphosphate (IPP). Until a few years ago it was believed that a single pathway from the Cg precursor mevalonic acid (MVA) formed IPP, which itself was synthesised from hydroxymethylglutaryl coenzyme A (HMG CoA) by the action of HMG... 

Sea cucumbers (Holothuroidea, Echinodermata) appear to be unique in their mode of squalene oxide (37) cyclization. Tritium-labeled lanosterol (33), cycloartenol (32) and parkeol (38) were individually administered to the sea cucumber Holothuria arenicola. While the former two triterpenes were not metabolized [22], parkeol was efficiently transformed into 14x-methyl-5a-cho-lest-9(l l)-en-3/ -ol (39) (Scheme 3). Other A1 sterols present in H. arenicola were not found to be radioactive and were thus assumed to be of dietary origin. The intermediacy of parkeol was confirmed by the feeding of labeled mevalonate (23) and squalene (26) to the sea cucumber Stichopus californicus [15]. Both precursors were transformed into parkeol, but not lanosterol nor cycloartenol, aqd to 4,14a-dimethyl-5a-cholest-9(ll)-en-3/J-ol (40) and 14a-methyl-5a-cholest-9(ll)-en-3/ -ol. Thus, while all other eukaryotes produce either cycloartenol or lanosterol, parkeol is the intermediate between triterpenes and the 14-methyl sterols in sea cucumbers. 

In more recent studies the use of HPLC allowed isolation and counting of individual sterols after administration of labelled precursors. The sterols isolated from mantles and viscera of the nudibranch Doris verrucosa were identified as cholestanol, cholesterol, 24-dehydrocholesterol and 7-dehydrocholesterol [103]. After injection of dl-[2-14C]-mevalonic acid DBED salt, cholesterol (57) and 7-dehydrocholesterol (58) were isolated as the acetates by reversed phase HPLC. Both sterols were found significantly labelled specific radioactivity associated with 7-dehydrocholesterol was higher by one order of magnitude than that associated with cholesterol. This fact would indicate either that the reduction of the A1 double bond of 7-dehydrocholesterol to afford cholesterol occurs at a low rate, or that the cholesterol found in D. verrucosa comes partly from a dietary source. 

Genetic analysis indicates that two of the 10 sad mutants of A. strigosa that we isolated represent different mutant alleles at the Sadi locus.6 These mutants accumulate radiolabelled 2,3-oxidosqualene but not p-amyrin when the roots are fed with 14C-labelled precursor mevalonic acid, suggesting that the triterpenoid pathway is blocked between 2,3-oxidosqualene and P-amyrin.34 The roots of these mutants also lack detectable P-amyrin synthase activity, but, like the wild type and the other mutants, are unimpaired in cycloartenol synthase (CS) activity and sterol biosynthesis.34 The transcript levels for AsbASl are substantially reduced in roots of sadl mutants, while AsCSl transcript levels are unaffected,35 suggesting that the sadl mutants are either mutated in the AsbASl gene itself or in a gene involved in its regulation. 

In nature, the biologically active form of acetic acid is acetyl-coenzyme A (acetyl-CoA) (see Box 7.18). Two molecules of acetyl-CoA may combine in a Claisen-type reaction to produce acetoacetyl-CoA, the biochemical equivalent of ethyl acetoacetate. This reaction features as the start of the sequence to mevalonic acid (MVA), the precursor in animals of the sterol cholesterol. Later, we shall see another variant of this reaction that employs malonyl-CoA as the nucleophile (see Box 10.17). 

It is generally agreed that mevalonate is the precursor to sterols in higher plants as well as in animals and is also the precursor to plant carotenoids. However, it is poorly incorporated into monoterpenes and into some diterpenes such as those of the taxane group.26 27 The alternative glyceraldehyde 3-... 

The Arabidopsis mutant dwf7/ste 1 is defective in C5-desaturation of episterol (Fig. (2)) [18], thus impaired in an enzyme function involved in a very early step of brassinosteroid precursor biosynthesis. The enzymatic block of dwf7/stel was determined by feeding experiments using l3C-labelled mevalonic acid and a subsequent analysis of endogenous sterol and brassinosteroid precursors. The mutant accumulates episterol with a simultaneous decrease of downstream intermediates (24-methylenecholesterol, campesterol, castasterone, brassinolide). 

The biochemical isoprene units may be derived by two pathways, by way of intermediates mevalonic acid (MVA) (Figure 5.4) or 1-deoxy-D-xylulose 5-phosphate (deoxyxylulose phosphate DXP) (Figure 5.6). Mevalonic acid, itself a product of acetate metabolism, had been established as a precursor of the animal sterol cholesterol, and... 

One of the more exciting and recent advances in the field of plant biochemistry has been the discovery of the mevalonate-independent pathway for the biosynthesis of isoprenoids (Fig. 10.4). This new pathway, referred to a the methyl-erythritol-phosphate or MEP pathway for the first intermediate committed solely to the biosynthesis of isoprenoids, was first discovered in prokaryotes capable of accumulating hopenes, the equivalent of eukaryotic sterols. 6,17 The MEP pathway has since been confirmed in plants and, not surprisingly, has been localized to chloroplasts.18 Operation of the MEP pathway is intimately related to the reactions of CO2 fixation and photosynthesis, as evidenced by the two immediate precursors pyruvate and phosphoglyceraldehyde for this pathway. Two important features of this pathway are that mevalonate is not an intermediate in the plastidic synthesis of isopentenyl (IPP) and dimethylallyl diphosphate, (DMAPP), and this pathway... 

Sterols are synthesized in nature from squalene and, therefore, ultimately from isoprene. Mevalonic acid is the immediate precursor of the isoprene unit, and the carboxylic acid group is lost as carbon dioxide when two mevalonic acid molecules combine head to tail. Thus, if the a carbon of mevalonic acid is labeled, then this carbon is always adjacent to the carbon bearing a side-chain methyl group. Examination of the way in which six isoprene units are linked in squalene (Example 6.2) shows that they are not all linked head to tail there is a point of symmetry in the structure of squalene (marked in the structure below). At this point a set of three isoprene units, linked head to tail, is joined head-to-head to a similar set of three isoprene units, to give the labeling pattern shown. 

Terpenoids are derived from the cytosolic mevalonate pathway or from the plastidial 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway (see also Terpenoid Biosynthesis). Both pathways lead to the formation of the C5 units isopentenyl diphosphate and its allylic isomer dimethylallyl diphosphate, which are the basic terpenoid biosynthesis building blocks (Fig. 1). Although increasing evidence suggests that exchange of intermediates occurs between these compartments, the cytoplasmic mevalonate pathway is generally considered to supply the precursors for the production of sesquiterpenes and triterpenes (including sterols) and to provide precursors for protein prenylation and for ubiquinone and heme-A production in mitochondria. In the plastids, the MEP pathway supplies the precursors for the production of isoprene, monoterpenes, diterpenes (e.g., GAs), and tetraterpenes (e.g., carotenoids). 

The so-called acetate-malonate pathway leads to three different kinds of natiu al products depending on the detailed pathway followed. Fatty acids result from a reductive pathway to be described here, but acetate and malonate are also precursors for the isoprenoids (terpenes and sterols) produced via mevalonic acid (Ce) and... 

Cholesterol is a steroid component of animal membranes and a precursor of steroid hormones. The committed step in its synthesis is the formation of mevalonate from 3-hydroxy-3-methylglutaryl CoA (derived from acetyl CoA and acetoacetyl CoA). Mevalonate is converted into isopentenyl pyrophosphate (C5), which condenses with its isomer, dimethylallyl pyrophosphate (C5), to form geranyl pyrophosphate (Cio). The addition of a second molecule of isopentenyl pyrophosphate yields farnesyl pyrophosphate (C15), which condenses with itself to form squalene (C30)- This intermediate cyclizes to lano-sterol (Cjq), which is modified to yield cholesterol (C27). 

Squalene has been shown to assume the folding pattern of Woodward and Bloch in the cyclization process that forms sterols (Fig. 17). This was demonstrated by the labehng patterns of sterols derived from acetate and mevalonate [90,91]. There are several ways by which squalene can cyclize, consequently it is the precursor of several polycyclic terpenoids (Chapter 7). The product depends on the conformation squalene assumes in binding to the cyclase and the nature and position of the nucleophiles and bases on the enzyme. Mechanistically, squalene requires an electrophilic attack at C-3 for cyclization to occur. This can be accomplished by direct attack of a as in the cycUzation that produces tetrahymanol and femene or by... 

DMAPP is a precursor of many isoprenoid compounds including carotenoids, sterols, and ubiquinones. IPP isomerase is an essential enzyme in organisms that use the mevalonate pathway to synthesize isoprenoid units, making the enzymes from S. pneumoniae and S. aureus interesting drug targets. 

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