Alkaloids tryptophan-derived alkaloid biosynthetic pathways

SCHEME 1.8 Tryptophan-derived alkaloid biosynthetic pathways (gray parts monoteipenic units). 

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 families Catenicellidae and Flustridae produce alkaloids derived from tryptophan. The majority of these contain bromine at carbon 6 of the indole ring, although some are more extensively brominated. The convolutamydines (brominated tryptophan derivates isolated from the genus Amathia in the order Ctenostomata)128 are similarly brominated at carbon 6, suggesting a common biosynthetic pathway or bacterial symbiont. 

Alkaloids thus represent one of the largest groups of natural products, with over 10,000 known compounds at present, and they display an enormous variety of structures, which is due to the fact that several different precursors find their way into alkaloid skeletons, such as ornithine, lysine, phenylalanine, tyrosine, and tryptophan (38-40). In addition, part of the alkaloid molecule can be derived from other pathways, such as the terpenoid pathway, or from carbohydrates (38-40). Whereas the structure elucidation of alkaloids and the exploration of alkaloid biosynthetic pathways have always commanded much attention, there are relatively few experimental data on the ecological function of alkaloids. This is the more surprising since alkaloids are known for their toxic and pharmacological properties and many are potent pharmaceuticals. 

The biosynthetic pathway to the ergoline nucleus proceeds through 4-dimethylallyl tryptophan (4-DMAT), chanoclavine-I, agroclavine, and lysergic acid. Two cis, trans isomerizations occur one before chanocla-vine-I and the other before agroclavine, as shown by experiments with [2- C]-mevalonic acid and [Z-CH3]-4-DMAT (Fig. 36). The peptide unit is derived from a combination of three amino acids, one of which is always proline. Several genera in the plant family Convolvulaceae Rivea, Ipomoea, etc.) also produce ergot alkaloids. 

In general, alkaloids derive from the metabohsm of amino acids such as phenylalanine (Phe), tyrosine (Tyr), tryptophan (Trp), omitine (Om), or lysine (Lys). Quinolizidine alkaloids derived from L-lysine. Its decarboxylation by means of the enzyme lysine decarboxylase gives cadaverine (Cad), the first detectable intermediate of this biosynthetic pathway (Scheme 14.1). 

Secondary metabolites are produced by plants in response to biotic or abiotic interactions with their environment and confer protection through a variety of antimicrobial, pesticidal, and pharmacological properties. Alkaloids are a class of plant secondary metabolites that traditionally have been classified as basic compounds derived firom amino acids that contain one or more heterocyclic nitrogen atom. About 20 % of plant species accumulate alkaloids, which are mostly derived from amino acids, e.g., phenylalanine, tyrosine, tryptophan, and lysine. The alkaloids are popular for their medicinal importance. The pharmaceutically important representatives of secondary metabolites are mostly alkaloids derived from tyrosine. In this chapter, we summarized the prior information, basic knowledge about the alkaloids, origin, physicochemical properties, uses, classification, biosynthetic reactions, and distribution of tyrosine-derived alkaloids especially opium alkaloids and their biosynthetic pathways in plants. We have also reviewed different web resources related to alkaloids and secondary metabolic pathway databases such as KEGG. 

An impressive body of evidence has established that these alkaloids are formed from L-tryptophan (7.25) which condenses at C-4 with dimethylallyl pyrophosphate (7.27), derived in the usual way from (3-7 )-mevalonic acid, to give dimethylallyltryptophan (7.52) [28] this is then modified to give, e.g. elymoclavine (7.55). The main biosynthetic pathway is (7.52) chanoclavine-I (7.55) — agroclavine 7.54) elymoclavine (7.55) lysergic acid (7.55) [27]. 

Actually there are no good definitions of alkaloids (Bate-Smith and Swain, 1966) since each one is either too narrow or too broad. Even in the restricted Winterstein and Trier definition, at least five alkaloid families exist that can be derived from different amino acids consequently, there is a need to establish the proper biosynthetic pathways to permit the application of the alkaloid character to chemotaxonomy, It has been mentioned above that canadine (berberidine) may be found in plants of six partially unrelated botanical families. This fact is not surprising when considered in relation to the biochemical investigations of canadine biosynthesis. Many reactions are necessary to convert tyrosine into canadine consequently, one might even wonder why the distribution of this alkaloid is so limited. In contrast, other plants (and even some that produce canadine) can produce many alkaloids that are derived from tyrosine but have a marked difference in structure. Tyrosine serves as the key precursor of alkaloids of the isoquinoline type, but other types of alkaloids, such as colchicine and the Amaryllidaceae and the Erythrina alkaloids, may be synthesized from this amino acid. The nucleus of an alkaloid molecule can arise from different precursors thus the indole nucleus in Erythrina alkaloids arises from tyrosine, while in brucine it comes from tryptophan (Figure 1.5). The alkaloids cinchonamine and cinchonine differ in that cinchonamine has an indole nucleus, while cinchonine (like quinine) has a quinoline nucleus however, they exist in a precursor-product relationship (that is, the quinoline type is derived from the indole type in a one-step reaction). 

Figure 1.6a. Structures of some Rutaceae alkaloids. This order is recognized for accumulating alkaloids derived from different biosynthetic pathways, e.g., from anthranilic acid, tyrosine, tryptophan, and histidine.

Another system which Floss et al. (1974) describe regulates alkaloid precursor synthesis, which had been studied to some extent in the ergot fungus Claviceps purpurea. The clavine ergot alkaloids are derived from tryptophan, mevalonic acid, and the methyl group of methionine (Weygand and Floss, 1963) in the biosynthetic pathway shown in Figure 6.35. Ross et al. (1974) and Arcamone et al. (1962) have studied the effect of various... 

Biosynthesis of some classes of terpene indole alkaloids is well understood. In certain cases, many of the enzymes that are responsible for biosynthesis have been cloned and mechanistically studied. In other cases, biosynthesis pathway is only proposed based on the results of feeding studies with isotopically labeled substtates and from the structures of isolated biosynthetic intermediates. All terpene indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Fig. 14.11). Tryptophan decarboxylase, a pyridoxal-dependent enzyme [29], converts tryptophan to tryptamine [30]. The following strictosidine synthase-catalyzed Mannich reaction connects ttyptamine and secologanin to yield strictosidine [31]. The Apocynaceae, Loganiaceae, Rubiaceae, and Nyssaceae families of plants each produce terpene indole alkaloids with dramatically diverse structures [32-34]. The mechanisms and control of... 

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