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3. Biosynthesis of pyrrolizidine alkaloids.

The biosynthetic routes were elucidated by a number of investigations performed with 2H-, 3H-, 13C-, 14C-, and 15N-labeled compounds. Both necine bases and necic acids are produced in the amino acid metabolism.

3.1. Biosynthesis of necines

As illustrated in Scheme 1 biosynthesis starts with decarboxylation of the amino acids L-arginine and L-ornithine by the action of arginine and ornithine decarboxylase leading to the formation of putrescine [30-37]. From two putrescine molecules homospermidine is formed. This step, the most important one in the biosynthesis of alkaloids, is catalyzed by the specific enzyme homospermidine synthetase (HS) [38-40]. Homospermidine is cyclized to the corresponding intermediate iminium ion which is reduced with further cyclization to the 1-hydroxymethylpyrrolizidines isoretronecanole and trachelanthamidine. Subsequent hydroxylation and dehydration afford retronecine which is usually a basic constituent of the toxic pyrrolizidine alkaloids. Otonecine, on the other hand, basic component of the otonecine alkaloids, is produced from retronecine, presumably by further hydroxylation and formation of a ketonic group with simultaneous cleavage of the C-N bond and N-methylation. In accordance with these steps is the observation that in cell cultures of Senecio vernalis after a certain period the content of senecionine N-oxide decreases while that of senkirkine, secondary product of otonecine, increases [41-43].

Fig. 6: Dicarboxylic acid used for the construction of 13-membered macrocyclic PAs
Fig. 6: Dicarboxylic acid used for the construction of 13-membered macrocyclic PAs

Amabiline
Amabiline

7-Angeloylretronecine
7-Angeloylretronecine

9-Angeloylretronecine
9-Angeloylretronecine

Echimidine
Echimidine

Monocrotaline
Monocrotaline

Senecionine

Senecionine

Senkirkine
Senkirkine

Doronenine
Doronenine

Parsonsine
Parsonsine

Fig. 7 Esterification possibilities of necines with mono- and dicarboxylic acids

Scheme 1: Biosynthesis of necines
Scheme 1: Biosynthesis of necines

3.2. Biosynthesis of necic acids

Necic acids are mainly composed of L-valine, L-leucine, L-isoleucine, and the secondary product of the latter, the L-threonine. In contrast to the necine biosynthesis the synthesis of necic acids follows different routes. In the threonine metabolism monocarboxylic acids with 5 C atoms such as angelic, tiglic and sarracinic acid are generated. Threonine the metabolism of which proceeds via a -ketobutyric acid can interact with pyruvate to furnish isoleucine which may be involved in the formation of necic acids. Isoleucine can be degraded to propionyl-Co A and acetyl-Co A via tiglyl-Co A. The different biosynthetic routes leading to these products are compiled in Scheme 2 [44-61].

Scheme 2: Biosynthesis of monocarboxylic acids
Scheme 2: Biosynthesis of monocarboxylic acids

Valine is converted into senecioic, viridifloric and trachelanthic acid via an acyloin reaction with activated acetaldehyde. The formation of the 10 C atom-containing dicarboxylic acids is only effected by subsequent cylization of the open-chain necine monocarboxylic acid diesters. Thus, according to Bourauel, senecionine is produced from diangeloylretronecine in a reaction similar to the Michael addition proceeding via kationic intermediates [62]. The different metabolic pathways thus enable a great variability in the formation of necic acids.

Scheme 3: Biosynthesis of dicarboxylic acids
Scheme 3: Biosynthesis of dicarboxylic acids

Biosynthesis takes place in the roots where the alkaloids occur as N-oxides. Being available in easily water-soluble form, they are transported to the aerial parts of the plant and stored there in vacuoles [63, 64].


Medicinal plants in Europe containing pyrrolizidine alkaloids was written by Prof. Dr. E. Röder and published in the journal "Pharmazie" 50 (1995), pages 83-98.



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