Alkaloids from Lysine

Just as terpenes could be viewed as being formed from isoprene units, alkaloids can be viewed as being derived from amino acids. Four amino acids give rise to important classes of alkaloids. As shown in Table 28.1, the pyrrolidine alkaloids are derived from the amino acid ornithine (not one of the 20 standard amino acids), the piperidine alkaloids from lysine, the isoquinoline alkaloids from tyrosine, and the indole alkaloids from tryptophan. 

Biosynthesis of piperidine alkaloids from lysine/cadaverine commonly occurs via A piperideine (31). Three molecules are utilized for the construction of lupanine (27), and an attractive biosynthetic route involving the all-trans-isomer of... 

Quinolizidine Alkaloids.—Previous results demonstrate that the quinolizidine skeleton in its entirety derives from lysine.Further research has indicated that lysine is a precursor of all the alkaloids of this type in five species of Leguminosae. From the levels of activity observed in the individual alkaloids it was concluded that saturated alkaloids are precursors for those with a pyridone ring. This was supported by the observation that label from radioactive sparteine (24) and lupanine (25) appeared in more highly oxidized alkaloids. (This compares with a similar situation in the biosynthesis of matrine-type alkaloids. ) A metabolic grid for the biosynthesis of quinolizidine alkaloids from lysine was proposed, based on these results,... 

The full paper on the biosynthesis of the lycopodium alkaloids from lysine was published.29 xhe possibility that two identical pelletierine units (20). derived from lysine and acetate, would combine to form lycopodlne (21) was not corroborated by double labeling experiments with [4,5-%2 2" "P ll tierine.30 Only the portion of the molecule drawn in heavy line was derived from pelletierine. 

Coniine (12), impHcated by Plato in the death of Socrates, is the major toxic constituent of Conium maculatum L. (poison hemlock) and, as pointed out eadier, was apparendy the first alkaloid to be synthesized. For years it was thought that coniine was derived from lysine (24), as were many of its obvious relatives containing reduced piperidine nuclei and a side chain, eg, peUetierine (46). However, it is now known (99) that coniine is derived from a polyketooctanoic acid [7028-40-2] (138), CgH QO, or some other similar straight chain analogue. 

The study above does not account for the extra six carbons acquired in the conversion of piperideine (8, 10 carbons) to phlegmarine (9, 16 carbons). It was initially proposed that the carbons were incorporated via pelletierine (12), which was incorporated twice into lycopodine resulting in two symmetrical halves of the alkaloid (Scheme 6.2). However, when 14C-labeled pelletierine (12, label at C2) was fed to the plant, degradation studies of lycopodine revealed that only one half consisted of the 14C label from pelletierine (the half containing C9-C16) [10]. The other half does not result from pelletierine 12 but must be something similar in structure since it does contain the piperideine unit (8) resulting from lysine. It was of interest then to determine the exact source of the three-carbon propionate unit in pelletierine (12). 

Fig. 5.1 Common cyanobacterial hepatotoxins. (a) Generalized structure of microcystin, a cyclic heptapeptide. Note that X and Z are L-amino acids. For example, microcystin-LR possesses lysine and arginine residues at X and Z, respectively, (b) Cylindrospermopsin, a hepatotoxic alkaloid from Cylindrospermopsis raceborskii...

The relationship between anemone fish, Amphiprion sp., and their sea anemone partners are regulated by alkaloids from the sea anemone. Amphiprion perideraion is attracted to the sea anemone Radianthus kuekenthali by the simple lysine-derived alkaloid amphikuemin (Fig. 12.6 Murata etal, 1986). Other simple alkaloids, aplysinopsin and dihydroaplysinopsin, also attract A. perideraion, regulate its swimming rate and induce their species-specific partnership. A related anemone fish, Amphiprion ocellaris, is attracted to the sea anemone Stoichactis kenti by tyramine (Fig. 12.6) and tryptamine induces searching by the fish (Murata etal, 1986). 

The simple piperidine alkaloid coniine from poison hemlock is not derived from lysine, but originates by an animation process and is discussed on page 381. 

Quinolizidine Alkaloids.—Biosynthesis of quinolizidine alkaloids, e.g. sparteine (28), is from lysine (15) by way of cadaverine (16), as shown in Scheme 4. Three cadaverine units (as indicated by the thickened bonds) are required for the construction of alkaloids such as sparteine (28).10 Although something has been discerned about the biosynthetic relationships of various quinolizidine alkaloids, the nature of early intermediates beyond cadaverine has remained quite elusive.10 Exciting new results obtained with crude enzyme preparations from cell suspension cultures of Lupinus polyphyllus indicate why this is so. 

Lupin Alkaloids.—The Ci5 lupin alkaloids, e.g. sparteine (9) and lupanine (10), are biosynthesized from three C5 units derived (as shown in Scheme 2) from lysine and... 

There are many pyrrolidine alkaloids derived from ornithine and another large family of piperidine alkaloids derived from lysine by similar pathways involving... 

The rather similar alkaloids anabasine and anatabine come from different biosynthetic pathways. Labelling experiments outlined below show the origin of one carbon atom from lysine and others from nicotinic acid. Suggest detailed pathways. (Hint. Nicotinic acid and the intermediate yoi have been using in Problem 3 in the biosynthesis of the piperidine alkaloid are both electrophilic at position 2. You also need an intermediate derived from nicotinic acid which is nucleophilic at position 3. The biosynthesis involves reduction.)... 

Lysine-Derived Alkaloids. Just as putrescine (36) derived from omitliine (23) is considered the pregenitor of the nucleus found in pyrrolidine-containing alkaloids, so cadaverine [462-94-2] (44), C5H14N2, derived from lysine (24) is the idealized pregenitor of the 1-dehydropiperidine [28299-36-7] nucleus (45), C5H9N, found in the pomegranate, Sedum, Lobelia, Lupin, and Lycopodium alkaloids (39). 

Alkaloid metabolism in lupine was proved by Wink and Hartmann to be associated with chloroplasts (34). A series of enzymes involved in the biosynthesis of lupine alkaloids were localized in chloroplasts isolated from leaves of Lupinus polyphylls and seedlings of L. albus by differential centrifugation. They proposed a pathway for the biosynthesis of lupanine via conversion of exogenous 17-oxosparteine to lupanine with intact chloroplasts. The biosynthetic pathway of lupinine was also studied by Wink and Hartmann (35). Two enzymes involved in the biosynthesis of alkaloids, namely, lysine decarboxylase and 17-oxosparteine synthetase, were found in the chloroplast stoma. The activities of the two enzymes were as low as one-thousandth that of diaminopimelate decarboxylase, an enzyme involved in the biosynthetic pathway from lysine to diaminopimelate. It was suggested that these differences are not caused by substrate availability (e,g., lysine concentration) as a critical factor in the synthesis of alkaloids. Feedback inhibition would play a major role in the regulation of amino acid biosynthesis but not in the control of alkaloid formation. 

There are three principal groups of alkaloids derived from ornithine nicotine, the pyrrolizidines, and the tropanes, all having significant biological effects. From lysine are derived the piperidine alkaloids... 

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