Alkaloids from Mevalonate

Nitrogenous Extractives 5.2J.2 Alkaloids from Mevalonate 5JJ,2J Spiraea Alkaloids... 

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. 

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... 

The results of an investigation of the biosynthesis of cyclobuxine D from [2- C, (4i )-4- Hi]mevalonic acid in Buxus sempervirens are consistent with the labelling pattern (39) and a biosynthetic pathway from cycloartenol via C-3 and C-20 ketonic intermediates/ Buxozine C (40) is a new alkaloid from B. semper-virens. ... 

The terpenoid moieties of indole alkaloids have been proved to arise from mevalonate. Although labelled acetate can be specifically incorporated into many terpenoid compounds via mevalonate it is not a specific precursor for... 

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). 

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-... 

Piperidine alkaloids a group of alkaloids containing the piperidine ring system. Simple P.a. are the alkyl substituted piperidines which occur sporadically. The other P.a. are classified according to their origin, e.g. Coninm alkaloids (see), Punica alkaloids (see), Sedum alkaloids (see) and Lobelia alkaloids (see). These various groups are structurally different and have different mechanisms of biosynthesis. Other P. a. are found in water lilies, and are biosynthesized from mevalonic acid (see Nuphara alkaloids). A de-hydropiperidine structure is present in the Areca alkaloids (see) and the Betalains (see). 

T.a. are biosynthesized from mevalonic acid, but the origin of the nitrogen is not known. They therefore differ from the iridoid, isoquinoline and indole alkaloids, in which a monoterpene is linked to an amino acid. 

Vinca alkaloids, Catharanthus alkaloids a group of about 60 iridoid indole alkaloids from Vinca (Catharanthus) spp. Structurally, they are tetra- or penta-cyclic indole derivatives with an iridoid component, e g. vindoline, [a]n -18° (CHCI3), m.p. 174-176°C, and vincamine, [ci]d + 41° (pyridine), m.p. 232-233 °C. These are accompanied in the leaves by small quantities (about 0.005%) of two dimeric V.a., i.e. Vinblastine (see) and fincristine (see) (Hg.). Tryptophan and mevalonic acid are biosynthetic precursors... 

Battersby A R 1970 Biosynthesis of terpenoid alkaloids. In Goodwin T W (ed) Natural substances formed biologically from mevalonic acid. Academic Press New York, 157-168... 

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-... 

Most of the necic acids are Cio-acids. Because they can apparently be divided into two isoprene units, they were originally believed to be derived from mevalonate, even though the oxidation patterns and mode of coupling of the Cs units were quite different from those of terpenoid compounds. Indeed, acetate and mevalonate were found not to be specific precursors for the Cio-necic acid portions of pyrrolizidine alkaloids (J4,123). All of the acids investigated so far have been shown to be formed from common branched-chain amino acids. 

The principal steps in the mechanism of polyisoprene formation in plants are known and should help to improve the natural production of hydrocarbons. Mevalonic acid, a key intermediate derived from plant carbohydrate via acetylcoen2yme A, is transformed into isopentenyl pyrophosphate (IPP) via phosphorylation, dehydration, and decarboxylation (see Alkaloids). IPP then rearranges to dimethylaHyl pyrophosphate (DMAPP). DMAPP and... 

The incorporation of acetate into the monoterpene unit of the indole alkaloids has recently been reexamined (176). Using [l,2- C2]acetate it was established that no intact incorporation occurred, and a similar labeling pattern to that from [2- C2]acetate was observed, i.e., C-3, C-4, C-20, C-22, and C-23. Extensive scrambling of the acetate occurred via the Krebs cycle to label the 1 and 2 positions of acetate prior to incorporation. [2- C]Mevalonate was incorporated equally into C-17 and C-22 of ajmalicine (39), indicating that an equilibration occurs at some point in the pathway, as had been established previously with radiolabeled precursors 176). 

The route of formation of the carbazole nucleus is still far from understood, and has been variously considered to arise from 3-prenylquinolone via a pathway involving shikimic acid (394) and mevalonic acid (MVA) (400) (Scheme 3.1) (1,112,362-366), anthranilic acid (397) and prephenic acid (404) via a pathway involving shikimic acid (394) (Scheme 3.2) (367), and also tryptophan (408) involving the mevalonate (400) pathway (Scheme 3.3) (133). All of these pathways lack experimental proof. However, based on the occurrence of the diverse carbazole alkaloids derived from anthranilic acid (397) in the family Rutaceae, the pathway... 

Alkaloid biosynthesis needs the substrate. Substrates are derivatives of the secondary metabolism building blocks the acetyl coenzyme A (acetyl-CoA), shikimic acid, mevalonic acid and 1-deoxyxylulose 5-phosphate (Figure 21). The synthesis of alkaloids starts from the acetate, shikimate, mevalonate and deoxyxylulose pathways. The acetyl coenzyme A pathway (acetate pathway) is the source of some alkaloids and their precursors (e.g., piperidine alkaloids or anthraniUc acid as aromatized CoA ester (antraniloyl-CoA)). Shikimic acid is a product of the glycolytic and pentose phosphate pathways, a construction facilitated by parts of phosphoenolpyruvate and erythrose 4-phosphate (Figure 21). The shikimic acid pathway is the source of such alkaloids as quinazoline, quinoline and acridine. 

In addition to acetyl-CoA, shikimic acid, mevalonic acid, and deoxyxylulose phosphate, other building blocks based on amino acids are frequently employed in natural product synthesis. Peptides, proteins, alkaloids, and many antibiotics are derived from amino acids, and the origins of the most important amino acid components of these are briefly indicated in Figure 2.1. Intermediates from the glycolytic pathway and the Krebs cycle are used in constructing many of them, but the aromatic amino acids phenylalanine, tyrosine,... 

It had already been stated earlier that clavine alkaloids are formed from L-tryptophan and mevalonic acid, the methyl group in position 6 originating from methionine (53, 54). There was also evidence that 4-dimethylallyltryptophan (3) is an early intermediate in the biosynthetic pathway (58). 

Daphniphyllum macropodum contains a great variety of related alkaloids whose structures are quite complex and novel (Section II). It is structurally evident that these alkaloids with an isopropyl or a potential isopropyl group are regarded as a terpene alkaloid. Bio-genetieally, these Daphniphyllum alkaloids, particularly C22 alkaloids, have been proposed to be derived from four molecules of mevalonic acid (MVA) and one acetate unit (15, 39). However, the recent tracer experiments showed that these alkaloids could be biosynthesized from six MVA molecules through a squalene-like intermediate. Accordingly, they should be included in a group of triterpene alkaloid. 

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