Catharanthus roseus biosynthesis

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

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. 

McCoy E, O Connor SE, Directed biosynthesis of alkaloid analogs in the medicinal plant Catharanthus roseus, J Am Chem Soc 128 14276-14277, 2006. 

Gene transfer from the angiosperm Catharanthus roseus, and over-expression in the bacterium Escherichia coli, yielded the synthase for strictosidine, a known alkaloid of the tryptophan-secologanin class (Scott 1992). A similar strategy has clarifted the biosynthesis of hydrogenobyrinic acid, an advanced precursor of vitamin B,2 (Scott 1994). 

Oudin A, Courtois M, Rideau M, Clastre M. The Iridoid Pathway in Catharanthus roseus Alkaloid Biosynthesis. Phytochemical Reviews 2007 6 259-276. 

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. 

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. 

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). 

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., 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. 

DETHIER, M., DE LUCA, V., Partial purification of an jV-methy 1 transfsrase involved in vindoline biosynthesis in Catharanthus roseus. Phytochemistry, 1993, 32, 673-678. 

DE CAROLIS, E., DE LUCA, V., Purification, characterization, and kinetic analysis of a 2-oxoglutarate-dependent dioxygenase involved in vindoline biosynthesis from Catharanthus roseus. J. Biol. Chem., 1993,268,5504-5511. 

ST-PIERRE, B., VAZQUEZ-FLOTA, F.A., DE LUCA, V., Multicellular compartmentation of Catharanthus roseus alkaloid biosynthesis predicts intercellular translocation of a pathway intermediate. Plant Cell, 1999, 11, 887-900. 

DE LUCA, V., CUTLER, A.J., Subcellular localization of enzymes involved in indole alkaloid biosynthesis in Catharanthus roseus. Plant Physiol., 1987, 85, 1099-1102. 

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.

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... 

The enzyme STR1 that was first characterized in Catharanthus roseus cell suspension cultures produces the central indole alkaloid intermediate H-3-a-(S)-strictosidine from tryptamine and secologanin (Fig. 8.9). It is well known that strictosidine represents the central intermediate precursor for several thousand indole alkaloids found in Nature. STR1 was the first gene to be cloned from R serpentina that involved a committed step in alkaloid biosynthesis.31 This was soon followed by the identification and isolation of an STR clone from Catharanthus roseus32 whose sequence was 80 % identical to the same gene from R serpentina.31... 

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. 

Tryptamine has been identified as a native compound in tomato,132 and the gene encoding tryptophan decarboxylase has been isolated from Catharanthus roseus,133 Plants grown on deuterium oxide incorporated more label into tryptamine than IAA, which was consistent with the result expected for a precursor of IAA. IAOx may be a YUCCA pathway intermediate for IAA biosynthesis in A. thaliana, and perhaps in rice and maize as well however, no enzyme has yet been identified for the conversion of A-hydroxyl tryptamine to IAOx. Because tryptamine is not a compound universally present in plants69 and deuterium oxide labeling ruled out tryptamine as an intermediate in tomato,132 the pathway would have to be species-specific. 

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.

Buriat, V., Oudin, A., Courtois, M., Rideau, M. and St. Pierre, B. (2004) Co-expression of three MEP pathway genes and geraniol-lO-hydroxylase in internal phloem parenchyma of Catharanthus roseus implicates multicellular location of intermediates during the biosynthesis of monoterpene indole alkaloids and isoprenoid-derived primary metabolites. Plant., 38,131 1. 

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. 

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