Ajmaline, biosynthesis

Pfitzner A, Stoeckigt J. Biogenetic link between sarpagine and ajmaline type alkaloids. Tetrahedron Lett. 1983 24 5197-5200. Gerasimenko I, Ma X, Sheludko Y, Mentele R, Lottspeich E, Stockigt J. Purification and partial amino acid sequences of the enzyme vinorine synthase involved in a crucial step of ajmaline biosynthesis. Bioorg. Med. Chem. 2004 12 2781-2786. 

Terpenoid Indole Alkaloids.—Important recent work has defined strictosidine (97) as a key intermediate in the biosynthesis of terpenoid indole alkaloids with both 3a- and 3/3-configurations. Some of this work, published earlier in preliminary form (cf. Vol. 9, p. 18), is now available in a full paper.26 In addition to those alkaloids examined earlier, strychnine, gelsemine, vincadifformine, isoreserpiline, aricine, isoreserpinine, and ajmaline have been shown to derive from strictosidine (data are also included for ajmalicine, for catharanthine, and for vindoline which had been reported earlier). 

SCHMIDT, D., STOCKIGT, J., Enzymatic formation of the sarpagan-bridge A key step in the biosynthesis of sarpagine- and ajmaline-type alkaloids. Planta Med., 1995,61,254-258. 

FALKENHAGEN, H., STOCKIGT, J., Enzymatic biosynthesis of vomilenine, a key intermediate of the ajmaline pathway, catalyzed by a novel cytochrome P450-dependent enzyme from plant cell cultures of Rauwoljia serpentina. Z. Naturforsch., 1995, 50C, 45-53. 

VON SCHUMANN, G., GAO, S STOCKIGT, J., Vomilenine reductase - a novel enzyme catalyzing a crucial step in the biosynthesis of the therapeutically applied antiarrhythmic alkaloid ajmaline. Bioorg. Med. Chem., 2002,10,1913-1918. 

Ruppert, M., Xueyan, M. and Stockigt, J. (2005) Alkaloid biosynthesis in Rauvolfia-cDNA cloning of the major enzymes of the ajmaline pathway. Curr. Org. Chem., 9, 1431-44. 

Stockigt J. Enzymatic biosynthesis of monoterpenoid indole alkaloids ajmaline, sarpagine and vindoline. Studies Organ. Chem. 1986 26 497-511. 

Gao S, von Schumann G, Stockigt J. A newly detectedreductase from Rauvolfia closes a gap in the biosynthesis of the antiar-rhythmic alkaloid ajmaline. Planta Med. 2002 68 906-911. 

Fig. 38 The biosynthesis of ajmaline, ajmalicine, a-yohimbine, reserpine, and rescinnamine.

Hie first, by Lounastnaa and Hanhinen, updates an area of indole alkaloids which has been neglected in the series for over 30 years, namely, the ajmaline group of alkaloids, where numerous advances in chemistry and biosynthesis have been made recently. The second chapter by Michael reports on the progress made in a vast area of alkaloid chemistry, those alkaloids with either an indolizidine or a quinolizidine nucleus derived from plant, marine animal, and fungal sources. 

The general role played by strictosidine (151) (Fig. 8) in the biosynthesis of all monoterpenoid indole alkaloids is firmly established (220-224). In the biogenetic formation of sarpagine (and ajmaline) alkaloids, the van Tamelen proposal (201,202) has been generally accepted (213,222,223), that is, that formation of a bond between C-5 and C-16 in the intermediate 4,5-... 

Protein biosynthesis is essential for all cells and thus provides another important target. Indeed, a number of alkaloids have been detected (although not too many have been studied in this context) which inhibit protein biosynthesis in vitro. Emetine from Cephaelis ipecacuanha (Rubiaceae) is the most potent plant constituent other alkaloids with the same ability include harringtonine, homoharringtonine, cryptopleurine, tubulosine, hemanthamine, lycorine, narciclasine, pretazettine, pseudolycorine, tylocrepine, and tylopherine [5] and furthermore, ajmaline, berberine, boldine, cinchonine, cinchonidine, harmalin, harmin, lobeline, norharman, papaverine, quinidine, quinine, salsoline, sanguinarine,... 

Ajmaline, because of its availability and facile transformations, remains the compound of choice as a convenient material for partial synthetic work. The continuing study of its biosynthesis is beginning to bear fruit and it is now certain that the hydroaromatic moiety of this type I base (f) is derived from a terpenoid percursor (4). 

The biosynthesis of ajmaline is illustrated as an example for the biosynthesis of a monoterpenoid indole alkaloid (see flgure). tit Pelletier 1, 2U-376. 

Figure Simplified scheme for the biosynthesis of the antiar- > rhythmic agent ajmaline. Only the key steps are shown in the scheme. The cofactors given on the left side participate in individual enzymatic reactions. The following enzymes were identified in the 15-step sequence leading to the final product ajmaline 1 strictosidine synthase 2 strictosidine glucosidase ...

Biosynthesis R. is derived from vomilenine, an intermediate in the biosynthetic pathway to the antiarrhyth-mic ajmaline, by glucosylation. The corresponding glucosyl transferase is membrane-bound, dependent on uridine diphosphate glucose, and has a high substrate specificity. A soluble, substrate-specific glu-cosidase effects the reversal of this reaction see also Rauvolfia alkaloids. 

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