Nicotine biosynthetic pathway

Hibi et al. " have reported on putrescine A-methyltransferase isolated from the nicotine biosynthetic pathway coded by cDNA. Recent advances in cell and molecular biology of alkaloid biosynthesis have heightened awareness of the genetic importance. 

The biosynthetic pathway to both nicotine (5) and the tropane alkaloids includes A-methylputrescine (4) as a probable intermediate. New results6 obtained for nicotine (5) and scopolamine (6) with 1 l-13C,14C wef/zy/awmo-15Nl-A-methyl putrescine 1(4) labels as shown nicely confirm this. The specific incorporation of both stable isotopes was closely similar to that of the 14C label in both alkaloids, indicating intact incorporation of the precursor. The labelling patterns deduced are illustrated ( = 13C, = 15N), and they are in accord with earlier results that were... 

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.)... 

In fhe early 1980s, root cultures of Nicotiana, Hyoscyamus, Datura and Duboisia species were found fo give high yields of nicotine and tropane alkaloids and have proved useful fools for recent studies of the biosynthetic pathways to these alkaloids. Genetically transformed and untransformed root cultures have been generated and used as models for biosynthetic studies (Rhodes et al, 1990 Robins et al, 1994a,b Wildi and Wink, 2002). 

A-methylputrescine oxidase catalyzes the formation of N-methylpyrrolinium cation, an important intermediate of tropane alkaloids biosynthetic pathway as well as of nicotine. Fig. (1). The... 

In many cases, the volatile compounds emitted from leaves as a result of insect damage allow insect parasitoids and predators to distinguish between infested and uninfested plants, and therefore help to locate hosts or prey [230]. In the majority of plants reported so far, there are remarkable similarities in the structure of VOCs that are emitted from insect-damaged leaves [231]. This structural uniformity suggests the activation of a common set of biosynthetic pathways shared by a wide range of plants, and that the products are detectable by a broad spectrum of insect parasitoids and predators. For instance, nicotine is one of the most broadly effective plant defence metabolites known because it poisons acetylcholine receptors and is thus toxic to most heterotrophic organisms with neuromuscular junctions. 

It is now accepted that iV-methyl-A1 -pyrrolinium salt is the common precursor of not only tropane alkaloids but also of the N-methylpyrrolidine ring of nicotine, hygrine and cuscohygrine, as shown in Fig. 4. Purification of several enzymes involved in the tropane alkaloid synthesis and the use of radiolabelled precursors have considerably improved our understanding of the biosynthetic pathway. 

The most accepted biosynthetic pathways for piperidine is lysine via A -piperidine (3973, 17B05). Piperidine can also be formed through decarboxylation and dehydrogenation of nicotinic acid (17B37). 

There is an alternative way of viewing the above results, however. It could be that the biosynthetic pathway to the pyrrolidine ring of nicotine is similar (in part) to the route to the piperidine alkaloids. Part of the model suggested for the biosynthesis of the piperidine nucleus from lysine (see above) could be easily adapted to account for the C02 and nornicotine results, that is variable/in-complete equilibration of bound putrescine (arising by enzyme-mediated decarboxylation of ornithine) with unbound material. L-Ornithine decarboxylase (EC 4.1.1.17, L-ornithine carboxy-lyase) occurs widely in higher plants and like L-lysine decarboxylase requires pyridoxal phosphate as a co-factor. ... 

Pelletierine is biosynthesized through the incorporation of lysine. Among the several types of alkaloid possessing the piperidine nucleus, lobeline involves a similar biosynthetic pathway (Section 4.4) as that of pelletierine, whereas arecoline and coniine are biosynthesized through completely different pathways. The former alkaloid is derived lirom nicotinic acid (Section 10.3), and the latter alkaloid is biosynthesized via the polyketide pathway (Section 15.1). 

It was already described in Section 3.1 that ornithine is incorporated into nicotine in the form of a symmetrical intermediate, putrescine. Although the last stages in the biosynthesis of (-)-anabasine are potentially quite similar to those of (-)-nicotine, during this biosynthetic pathway, it is considered that a symmetrical intermediate, such as cadaverine, is not involved.Thus, when [2- C]lysine was incorporated into (-)-anabasine, was introduced only into the C-2 position of the piperidine ring of... 

Although the chemical structure of (-)-anatabine is quite similar to that of (-)-anabasine, remarkably, the biosynthetic pathways of these alkaloids are considerably different. Thus, (-)-anabasine is biosynthesized from nicotinic acid and lysine as described above, whereas, (-)-anatabine is biosynthesized from two molecules of nicotinic acid [2,3], as described in Chapter 10. 

On the other hand, when [6- H]nicotinic acid was fed to the above system, the total amount of was considerably decreased compared with the result when [2— H], [4- H], or [5- H]nicotinic acid was used as a precursor. This supports the idea that 3,6-dihydronicotinic acid exists as an intermediate in the biosynthetic pathway. The stage at which decarboxylation occurs has not been finally clarified, but it seems that it is in concert with the condensation reaction of 3,6-dihydronicotinic acid with A -pyrroHdine or A -piperidine, because the label from [2— C]nicotinic acid remains at the C-2 of nicotine and is not randomized between C-2 and C-6 through the involvement of a symmetrical intermediate. 

---