Derivation from mevalonic acid

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. 

The isopentenyl pyrophosphate [l] derived from mevalonic acid isomerized into dimethyl allyl pyrophosphate [2] and... 

Several metabolic pathways for the biosynthesis of aromatic compounds are now known, (a) The aromatization of alicyclic and isoprenoid compounds derived from mevalonic acid, as in the formation of estrone (I) from testosterone (II). A very common example of this process, which has not yet been experimentally demonstrated, is probably the aromatization of a O OH... 

The biosynthesis of the ergot alkaloids involves condensation of dimethyl-allyl pyrophosphate (derived from mevalonic acid) with tryptophan. Closure of the C- and D-rings of the alkaloid involves specific hydroxylations by cytochrome P450-dependent oxidases and rearrangements. Further modifications involve N-methylation in the presence of S-adenosyl methionine and/or condensation with amino acids and peptides. Coupling of lysergyl CoA with certain peptides forms the peptide alkaloids which are the most bioactive of the ergot alkaloids. 

Most terpenoids are derived from mevalonic acid (MVA) through the universal precursor isopentenyl diphosphate (IPP) and its allylic isomer dimethylallyl diphosphate (DMAPP). Thus, the vast majority of terpenoids contain the basic structural residue 2-methylbutane, often less precisely referred to as isoprene units. These C5 hemiterpene units combine with... 

Many natural products contain an isolated isoprene unit derived from mevalonic acid hence, these compounds may be considered as hemiterpenoid derivatives. In most cases the immediate precursor is probably dimethyl allyl pyrophosphate... 

The early steps in the ergot alkaloid biosynthetic pathway are outlined in Fig. 1. The first determinant and rate-limiting step is the prenylation of tryptophan to 4-(y,y-dimethylallyl)tryptophan (DMAT), catalyzed by dimethy-lallyl-diphosphate L-tryptophan dimethylallyltransferase (DMAT synthase EC 2.5.1.34) (Heinstein et al., 1971 Gebler and Poulter, 1992). The prenyl group for the DMAT synthase reaction is provided in the form of dimethylallyl diphosphate (DMAPP), which is derived from mevalonic acid. After the formation of DMAT, the free amino group of this intermediate is N-methylated with a methyl group donated by S-adenosylmethionine (AdoMet). The N-methylated DMAT is then converted into chanoclavine I by closure of the... 

Cellular metabolites derived from mevalonic acid are required for cell proliferation. Cholesterol Is an essential component of cell membranes, farnesyl pyrophosphate is required to covalently bind to intracellular proteins and modify their function, ubiquinone is required for mitochondrial electron transport, and dolichol phosphates are required for glycoprotein synthesis. 

The isoprenoids are derived from mevalonic acid (MVA), which is formed from three molecules of acetyl-CoA (Fig. 3). Two molecules of acetyl-CoA are condensed, yielding acetoacetyl-CoA. Subsequently, this product is coupled with another molecule of acetyl-CoA to yield 35-hydroxy-3-methylglutaryl-CoA (HMG-CoA). By reduction of HMG-CoA MVA is obtained. MVA is further converted in some steps to yield the Cs-unit isopentenyl diphosphate (IPP), which is then isomerized to dimethy-lallyl diphosphate (DMAPP), the starter molecule of the isoprenoid pathway. Coupling of DMAPP with one or more IPP molecules yields the basic structures which form the backbone of terpenoid biosynthesis. A number of reviews on the early steps in the terpenoid biosynthesis have been published (70-77). 

The steroids are another group of compounds derived from mevalonic acid. They inciude i synthesis of the steroids is sex hormones such as testosterone and progesterone, and the cholesterol needed to build cell discussed in the online chapter membranes but also implicated in the damage to arteries caused by atherosclerosis. Natural products. ... 

With the possibility of the 1-deoxyxylulose 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway to the hemiterpene units, IPP and DMAPP, operating in higher plants, it will be of interest to establish whether the five-carbon unit incorporated into the quinoline nucleus is preferentially derived from mevalonic acid or 1 -deoxyxylulose. 

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-... 

Some commonly encountered five-carbon units are not derived from mevalonic acid. These moieties are found in such diverse groups as pyrrolizidine alkaloids and cyanolipids. Tiglic (15) and angelic (16) acids and their derivatives are widespread (Buckles et al., 1955). These compounds are derived in plants from leucine (Fig. 18.8). 

Carotenoids are C40 polyolefinic metabolites derived from mevalonic acid. Almost all members of this group are acyclic or have chains that terminate with one or two 6-membered rings. All have ttie potential for a vast number of geometric isomers, but, in practice, almost all have entirely E (trans) configurations many carotenoids are colored because of the extended conjugated systems they contain. The structures for approximately 500 carotenoids are known, but only about one-fourth of these are from plants (Britton, 1983). The leaves of all green plants contain the same major carotenoids 3-carotene (usually 25-30% of the total) (1), lutein (about 45%) [(3/ ,3 / ,6 / )-3, -carotene-3,3 -diol] (2), violaxanthin [(3S,5R,6S,3 S,5% 6 5)-5,6,5, 6 -diepoxy-... 

Aglycones are derived from mevalonic acid, but the final molecules arise from a condensation of a C21 steroid with a C2 unit (cardeno-lides) or C3 unit (bufadienolides). 

The purine nucleus is very probably furnished by the usual route of purine biosynthesis (page 156). The origin of the substituents on the amino group was investigated for IPA. The isopentenyl residue is derived from mevalonic acid. The site of biosynthesis is the roots. 

Lophocerine (19) derives from tyrosine and the C5 unit, formed from C-1 and the pendant isobutyl group, derives from mevalonic acid. In contrast to the isoquinoline alkaloids just discussed the molecule which condenses with a phenethylamine inter-... 

This very unusual lactone is assembled from three units 1. A sesquiterpenoid diol termed verrucarol (II), which is a hydroxylation product of trichodermol (III see p. 141) at the starred carbon atom 2. cis, frans-muconic acid (IV) 3. V, an isomer of mevalonic acid which is probably derived from mevalonic acid but not via isopentenyl pyrophosphate, and is thus probably not a terpenoid. 

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