Tabersonine biosynthesis

Tabersonine is derived from strictosidine through a series of yet uncharacterized pathway via an intermediate cathenamine. The genes related to tabersonine biosynthesis as well have been an unexplored area [33]. 

DE LUCA, V., BALSEVICH, J TYLER, R.T., EILERT, U PANCHUK, B.D., KURZ, W.G.W., Biosynthesis of indole alkaloids Developmental regulation of the biosynthetic pathway from tabersonine to vindoline in Catharanthus roseus. J. Plant Physiol., 1986,125, 147-156. 

Fig. 8.1 Sequence of reactions and pathways involved in the biosynthesis of indole alkaloids in Catharanthus roseus. The dotted lines indicate multiple and/or uncharacterized enzyme steps. Tryptophan decarboxylase (TDC), Geraniol Hydroxylase (GH), Deoxyloganin synthase (DS), Secologanin Synthase (SLS) Strictosidine synthase (STR1), Strictosidine glucosidase (SG), Tabersonine-16-hydroxylase (T16H), Tabersonine 6,7-eposidase (T6,7E), Desacetoxyvindoline-4-hydroxylase (D4H), Deacetyl-vindoline-4-O-acetyltransferase (DAT) and Minovincinine-19-O-acetyltransferase (MAT) represent some of the enzyme steps that have been characterized.

Extensive studies to quantitate the production of indole alkaloids in Catharanthus roseus hairy root cultures have revealed that they accumulate several compounds including ajmalicine, serpentine, catharanthine, tabersonine, horhammericine, and lochnericine.27, 28 The presence of tabersonine in hairy roots has raised speculations that this intermediate in vindoline biosynthesis, together with catharanthine, is transported from this potential site of biosynthesis through the vasculature to the stem and to the leaves where tabersonine is further elaborated into vindoline within laticifers and/or idioblasts.26 However, oxidized derivatives of tabersonine, such as horhammericine and lochnericine, are present at 5 to 15 times the levels of tabersonine in hairy roots,27 and presumably this prevents their transport and/or use for vindoline biosynthesis. In this context, it would be interesting to... 

SCHRODER, G., UNTERBUSCH, E KALTENBACH, M SCHMIDT, J., STRACK, D., DE LUCA, V., SCHRODER, J., Light induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis tabersonine 16 hydroxylase., FEBSLett., 1999,458,97-102. 

Another all-carbon Diels-Alder reaction is proposed for the biosynthesis of the indole alkaloids tabersonine 1-6 and catharanthine 1-7 of the Aspidosperma and Iboga family [28-31]. The compounds are formed via strictosidine 1-3, the first nitrogen-containing precursor of the monoterpenoid indole alkaloids, and stemmadenine 1-4, which is cleaved to give the proposed intermediate dehy-drosecodine 1-5 with an acrylate and a 1,3-butadiene moiety (Scheme 1-1). 

Figure 2.11 Biosynthesis of vindoline, catharanthine and the dimeric alkaloids vinblastine and vincristine. T16H, tabersonine-16-hydroxylase OMT, 5-adenosylmethionine 16-hydroxy-tabersonine-O-methyltransferase NMT, 5-adenosylmethionine 16-methoxy-2,3-dihydro-3-hydroxymethyltabersonine-/ /-methyltransferase D4H, desacetoxy-vindoline-4-dioxygenase DAT, acetylcoenzyme A 4-0-deacetylvindoline-4-0-acetyltransferase.

As in morphine biosynthesis, the knowledge of the enzyme sequences allows a more detailed understanding of the localization of the enzymes (104). Strictosidine synthase (Fig. 2b) seems to be localized to the vacuole (105), and strictosidine glu-cosidase is believed to be associated with the membrane of the endoplasmic reticulum (73, 106). Tabersonine-16-hydroxylase is associated with the endoplasmic reticulum membrane (98) N-methyl transferase activity is believed to be associated... 

Schroder G, Unterbusch E, Kaltenbach M, Schmidt J, Strack 114. D, de Luca V, Schroder J. Light induced cytochrome P450 dependent enzyme in indole alkaoid biosynthesis tabersonine... 

Murata J, de Luca V. Localization of tabersonine 16-hydroxylase and 16-OH tabersonine 16-O-methyl transferase to leaf epidermal cells defines them as a major site of precursor biosynthesis in the vindoline pathway in Cafiiaranthus roseus. Plant J. 2005 44 581-594. 

The biosynthesis of tabersonine is shown as occurring with 17,20-bond formation before 7,21 largely on the mechanistic grounds evident in Scheme 10 experiments considered to point against such a transannular ring-closure can be interpreted in ways not in conflict with Scheme 10. 

Fig. (5). Biosynthesis of catharanthine and tabersonine from strictosidine, the central precursor of all terpenoid indole alkaloids. SGD strictosidine p-D-glucosidade.

Fig. (6). Biosynthesis of vindoline from tabersonine. T16H tabcrsonine 16-hydroxylase OMT i -adenosyl -/.-methionine 16-hydroxytabersonine - 16-O-methyltransferase NMT S-adenosyl - /.-methionine 16-methoxy - 2,3-dihydro-3-hydroxytabersonine - iV-methyltransferase D4H desacetoxy vindoline 4-hydroxylase DAT acetyl coenzyme A 4-O-deacetylvindoline 4-O-acetyltransferase.

Schroeder, G., E. Unterbusch, M. Kaltenbach, J. Schmidt, D. Strack, V. De Luca et al. (1999). Light-induced cytochrome P450-dependent enzyme in indole alkaloid biosynthesis Tabersonine 6-hydroxylase. FEBS Lett. 458, 97-102. 

Terpenoid indole alkaloid biosynthesis actually starts with the coupling of tryptamine and secologanin (Fig. 12). In the next step, a glucosidase splits off the sugar moiety and the reactive dialdehyde formed is further converted through different pathways to a cascade of products, including ajmalicine, catharanthine, tabersonine, and vindoline. 

The knowledge of the biosynthesis of catharanthine is very limited only some feeding experiments with labeled precursors have been described, quite some years ago. Qureshi and Scott (227-229) reported that catharanthine is formed from tabersonine fed to the plant. However, other groups have not been able to confirm these results (230-232). Corynantheine aldehyde (229) and geissoschizine fed to C. roseus plants were reported to be incorporated into catharanthine (233). From these experiments it is believed that the pathway goes from strictosidine via 4,21-dehydrogeissoschizine, stemmadenine, and dehydrosecodine (Fig. 16). Based on the structures, the involvement of tabersonine in the catharanthine pathway is not likely, despite the reports of its incorporation. So far, nothing is known about the enzymes involved in this pathway. 

The biosynthesis of the terpenoid indole alkaloids in C. roseus has been studied extensively, but still the pathway has not yet been completely elucidated on the level of the intermediates. Particularly, the secoiridoid pathway, and the different pathways after strictosidine leading to, for example, tabersonine and catharanthine are not yet completely known. On the level of the enzymes, certain steps have now been quite well characterized, but others remain unknown. The conversion of loganin into secologanin is one of the intriguing unresolved problems, although it is not a rate-limiting step. Even possible intermediates and the chemical mechanism behind this conversion are not clear, despite quite extensive studies. 

Biosynthesis The biosynthesis of V., and especially the final stage of a ca. 15-step chain of reactions, has been studied on the enzymatic level The last 6 reactions, beginning at the level of the Catharanthus alkaloid "ta-bersonine are accordingly hydroxylations, methyla-tions, and acetylation. The final reaction in the biosynthesis of V. is catalyzed by a highly specific acetyl-CoA-dependent acetyltransfeiase which converts deacetylvindoline to V. Although catharanthine and ta-bersonine can be produced in cell cultures of C. roseus, the biosynthesis of V. in these cell systems is interrupted at the stage of tabersonine thus the dimeric in-... 

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