Catharanthus roseus indole alkaloid biosynthesis

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.

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. 

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. 

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.

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. 

Enzymes Characterized in Monoterpenoid Indole Alkaloid Biosynthesis in Catharanthus roseus ... 

O. J. M. Goddijn, Regulation of terpenoid indole alkaloid biosynthesis in Catharanthus roseus." Ph.D. Thesis, Leiden University, 1992. 

Chapter 3, by Verpoorte, van der Heijden, and Moreno, summarizes the tremendous progress achieved in the past twenty years in the use of cell culture systems to delineate and express the pathway of monterpene indole alkaloid biosynthesis in Catharanthus roseus. The authors review the formation of the precursor units and then examine the enzymatic aspects of secondary metabolism. They conclude with an overview of the influence of exogenous materials on the regulation of alkaloid biosynthesis. 

Salim V, De Luca V. Towards complete elucidation of monoterpene indole alkaloid biosynthesis pathway Catharanthus roseus as a pioneer system. In Advances in Botanical Research - New Light on Alkaloid Biosynthesis and Future Prospect. 2013. p. 1-37. 

Salim V, Yu F, Altarejos J, DeLuca V (2013) Virus-induced gene silencing identifies Catharanthus roseus 7-deoxyloganic acid-7-hydroxylase, a step in iridoid and monterpene indole alkaloid biosynthesis. Plant J 76 754-765... 

Shukla AK, Shasany AK, Verma RK, Gupta MM, Mathur AK, Khanuja PSP (2010) Influence of cellular differentiation and elicitation on intermediate and late steps of terpenoid indole alkaloid biosynthesis in Catharanthus roseus. Protoplasma 24 35-47. doi 10.1007/s00709-010-0120-1... 

Liu, D.H. et al. (2007) Terpenoid Indole Alkaloids biosynthesis and metabolic engineering in Catharanthus roseus. JIntegrat. Plant Biol. 49, 961-974... 

Kulshrestha, M., Patra, B. et al. (2011) The transcription factor CrWRKYl positively regulates the terpenoid indole alkaloid biosynthesis in Catharanthus roseus. Plant Physiol, 157, 2081-2093. 

Salutaridinol 7-0-acetyltransferase catalyzes the conversion of the phenanthrene alkaloid salutaridinol to salutaridinol-7-Oacetate, the immediate precursor of thebaine along the morphine biosynthetic pathway in P. somniferum (Fig. 10.7).26 Acetyl CoA-dependent acetyltransferases have an important role in plant alkaloid metabolism. They are involved in the synthesis of monoterpenoid indole alkaloids in medicinal plant species such as Rauwolfia serpentina. In this plant, the enzyme vinorine synthase transfers an acetyl group from acetyl CoA to 16-epi-vellosimine to form vinorine. This acetyl transfer is accompanied by a concomitant skeletal rearrangement from the sarpagan- to the ajmalan-type (reviewed in2). An acetyl CoA-dependent acetyltransferase also participates in vindoline biosynthesis in Catharanthus roseus, the source of the chemotherapeutic dimeric indole alkaloid vinblastine (reviewed in2). Acetyl CoA deacetylvindoline 4-O-acetyltransferase catalyzes the last step in vindoline biosynthesis. A cDNA encoding acetyl CoA deacetylvindoline 4-0-acetyltransferase was recently successfully isolated.27... 

Higher plants are a very important source of medicinally useful compounds. Catharanthus roseus is one of the most important of these plants, and this chapter focuses on the further isolation work directed at the identification of new potentially more active and/or less toxic bisindole alkaloids. In addition, the biosynthesis of the indole alkaloids of C. roseus is reviewed. While the former area of research has been dominated by sophisticated high-field NMR and high-resolution mass spectral analyses. 

Catharanthus roseus, biosynthesis of terpenoid indole alkaloids in, 49, 222 (1997) Celastraceae alkaloids, 16, 215 (1977)... 

Verpoorte R, van der Heijden R and Moreno PRH (1997) Biosynthesis of terpenoid indole alkaloids in Catharanthus roseus cells. The Alkaloids, Chemistry and Pharmacology (ed Cordell GA) Vol 49. Academic, San Diego, pp 221-299. 

Terpenoid Indole Alkaloids.—Current knowledge on the biosynthesis of terpenoid indole alkaloids, with particular emphasis on the very important results obtained with enzyme preparations from tissue cultures of Catharanthus roseus, has been authoritatively reviewed.53 Further work on cell lines of C. roseus that are able to produce Aspidosperma-type alkaloids has been published54 (cf. Vol. 11, p. 19). 

A large amount of structural information is available that describes the variety of indole alkaloids produced in plants. This has recently been followed by significant increases in our knowledge of the biosynthetic pathways that lead to their production and of the genes involved. Several reviews have appeared recently that describe the chemistry, biochemistry, cell and molecular biology of alkaloid biosynthesis.1 3 This chapter will selectively review recently characterized genes that appear to be responsible for the diversity and complexity of monoterpenoid indole alkaloids produced by plants. A particular focus will be on the reactions leading to the biosynthesis of vindoline (Fig. 8.1) in Catharanthus roseus. 

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.

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