Indole alkaloids, biosynthesis

9 BIOCHEMICAL AND MEDICINAL CHEMISTRY 5.2.9.1 Indole Alkaloid Biosynthesis 

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Bracher, D. and Kutchan, T. M. 1992. Strictosidine synthase from Rauvolfia serpentina Analysis of a gene involved in indole alkaloid biosynthesis. Archives of Biochemistry and Biophysics, 294 717-723. 

Cathenamine (100) has been identified as an early intermediate in terpenoid indole alkaloid biosynthesis (cf. Vol. 8, p. 27). It has also been isolated from Guettarda eximia. Another alkaloid, 4,21-dehydrogeissoschizine (99), has now been isolated from this plant it is readily converted into (100) in alkaline solution.29 On incubation with an enzyme preparation from Catharanthus roseus cell cultures in the presence of NADPH at pH 7, (99) was converted into ajmalicine (102), 19-ep/-ajmalicine (103), and tetrahydroalstonine (104), which are the normal products with this enzyme preparation. In the absence of NADPH, cathenamine (100) accumulated.30 The reaction to give (100) proceeded linearly with time, and was dependent on the concentration of protein and substrate. No conversion occurred in the absence of enzyme. 

Figure 7.9 Intercellular and subcellular trafficking in alkaloid biosynthesis. A. Tropane alkaloid biosynthesis in Hyoscyamus muticus. B. Terpenoid indole alkaloid biosynthesis in Catharanthus roseus. C. Trafficking of the berberine bridge enzyme in Papaver somniferum cell cultures.

COLLU, G., UNVER, N., PELTENBURG-LOOMAN, A.M.G., VAN DER HEIJDEN, R., VERPOORTE, R MEMELINK, J., Geraniol 10-hydroxylase, a cytochrome P450 enzyme involved in terpenoid indole alkaloid biosynthesis. FEBSLett., 2001, 508,215-220. 

IRMLER, S., SCHRODER, G., ST-PIERRE, B CROUCH, N.P., HOTZE, M., SCHMIDT, J., STRACK, D MATERN, U., SCHRODER, J Indole alkaloid biosynthesis in Catharanthus roseus new enzyme activities and identification of cytochrome P450 CYP72A1 as secologanin synthase. Plant J., 2000,24, 797-804. 

GEERLINGS, A., MARTINEZ-LOZANO IBANEZ, M., MEMELINK, J., VAN DER HEIJDEN, R., VERPOORT, R., Molecular cloning and analysis of strictosidine P-D-glucosidase, an enzyme in terpenoid indole alkaloid biosynthesis in Catharanthus roseus. J. Biol. Chem., 2000,275,3051-3056. 

DE LUCA, V., FERNANDEZ, J.A., CAMPBELL, D., KURZ, W.G.W., Developmental regulation of enzymes of indole alkaloid biosynthesis in Catharanthus roseus. Plant Physiol, 1988, 86,447-450. 

BIOCHEMISTRY AND MOLECULAR BIOLOGY OF INDOLE ALKALOID BIOSYNTHESIS THE IMPLICATION OF RECENT DISCOVERIES... 

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. 

MEIJER, A.H., VERPOORTE, R., HOGE, J.H.C., Regulation of enzymes and genes involved in terpenoid indole alkaloid biosynthesis in Catharanthus roseus. J. Plant Res., 1993, Special Issue 3, 145-164. 

Biochemistry and Molecular Biology of Indole Alkaloid Biosynthesis The... 

Figure 2.12 A hypothetical view of compartmentation of indole alkaloid biosynthesis in Catharanthus roseus. Enzymes located with dashed arrows are hypothetical and circles indicate membrane associated enzymes (after Meijer et at, 1 993b). Cl OH, geraniol-1 0-hydroxylase NMT, 5-adenosyl-L-methionine 11 -methoxy 2,16-dihydro-16-hydroxytabersonine N-methyltransferase DAT, acetylcoenzyme A deacetylvindoline 1 7-0-acetyltransferase OHT, 2-oxyglutarate-dependent dioxygenase SSpC, strictosidine-((3)-glucosidase SSS, strictosidine synthase.

De Luca, V. (1993) Enzymology of indole alkaloid biosynthesis, in Methods in Plant Biochemistry (ed. P.J. Lea), Vol. 9. Academic Press, London, pp. 345-67. 

Goddijn, O.J.M. (1992) Regulation of terpenoid indole alkaloid biosynthesis in Catha-ranthus roseus the tryptophan decarboxylase gene. Ph.D. Thesis, Leiden University. 

Rischer, H., Oresic, M., Seppanen-Laakso, T., Katajamaa, M., Lammertyn, R, Ardiles-Diaz, W., von Montagu, M.C.E., Inze, D., Oksman-Caldentey, K.-M. and Goosens, A. (2006) Gene-to-metabolite networks for terpenoid indole alkaloid biosynthesis in Catharanthus roseus cells. Proc. Natl. Acad. Sci. USA, 103,5614—9. 

Early steps of terpenoid indole alkaloid biosynthesis... 

Cyclopentanoid Monoterpenoids.—Further studies confirm that mevalonic acid, but not 3-hydroxy-3-methylglutaric acid, is specifically incorporated into loganic acid (27), and methionine or adenosylmethionine into loganin (28). The latter metabolite is a key intermediate in indole alkaloid biosynthesis. ... 

Rapid advances have been made in the study of the relatively rare cyclopentanoid monoterpenoids due to their involvement in indole alkaloid biosynthesis. The bismonoterpenoid foliamenthin (26) was discovered in these studies and Arigoni and co-workers have demonstrated the efficient incorporation of geraniol (27) into both halves of (26). Battersby obtained similar results with 6,7-dihydro-foliamenthin. In both cases, as expected, the acyclic half is more radioactive. 

Eburnamine-Vincamine Alkaloids.—So far most of the effort on indole alkaloid biosynthesis has been concentrated on the Corynanthe, Aspidosperma, and Iboga systems. It is welcome, therefore, to see the preliminary results of an investigation of the biosynthesis of vincamine (10).6 Comparable incorporations were observed for [ar-3H]tryptophan, [ar-3H]stemmadenine (5), and [ar-3H]taber-sonine (9). These results support the proposal7 that vincamine is a transformation... 

The proposal that the next stages of the pathway would involve intermediates of the Corynanthe type has received experimental support. Corynanthealdehyde (12) was not incorporated but the closely related corynantheal (13) did serve as an efficient precursor for all three Cinchona bases.12 Thus, the close parallel between the early stages of quinine biosynthesis and the corresponding stages (Scheme 1) of indole alkaloid biosynthesis is established. 

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