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Vinca Drug Components Accumulate Exclusively in Leaf Exudates of Madagascar Periwinkle

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Vinca Drug Components Accumulate Exclusively in Leaf Exudates of Madagascar Periwinkle Vinca drug components accumulate exclusively in leaf exudates of Madagascar periwinkle Jonathan Roepkea,1, Vonny Salima,1, Maggie Wua, Antje M. K. Thamma, Jun Muratab, Kerstin Plossc, Wilhelm Bolandc, and Vincenzo De Lucaa,2 aDepartment of Biological Sciences, Brock University, St. Catharines, ON, Canada L2S 3A1; bSuntory Institute for Bioorganic Research, Osaka 618 8503, Japan; and cMax-Planck-Institut für Chemische Ökologie, 07745 Jena, Germany Edited by Jerrold Meinwald, Cornell University, Ithaca, NY, and approved July 16, 2010 (received for review October 6, 2009) The monoterpenoid indole alkaloids (MIAs) of Madagascar peri- loganic acid O-methyltransferase (LAMT) and secologanin syn- winkle (Catharanthus roseus) continue to be the most important thase that catalyze the terminal reactions in secologanin bio- source of natural drugs in chemotherapy treatments for a range of synthesis are expressed exclusively within the epidermis of young human cancers. These anticancer drugs are derived from the cou- leaves and stems (13). This suggests very strongly that an un- pling of catharanthine and vindoline to yield powerful dimeric characterized pathway intermediate is transported between IPAP MIAs that prevent cell division. However the precise mechanisms and epidermal cells to elaborate the secologanin molecule. The for their assembly within plants remain obscure. Here we report epidermis of leaves, stems, and flower buds also express trypto- that the complex development-, environment-, organ-, and cell- phan decarboxylase (8, 14), strictosidine synthase (8, 14), stric- specific controls involved in expression of MIA pathways are cou- tosidine β-glucosidase (14), tabersonine 16-hydroxylase (14) and pled to secretory mechanisms that keep catharanthine and vindo- 16-hydroxytabersonine 16-O-methyltransferase (16-OMT) (14, 15), line separated from each other in living plants. Although the entire whereas the N-methyltransferase, dioxygenase, and acetyltransfer- production of catharanthine and vindoline occurs in young devel- ase (8, 14) responsible for the last three steps in vindoline biosyn- oping leaves, catharanthine accumulates in leaf wax exudates of thesis are expressed within leaf mesophyll cells or in specialized leaves, whereas vindoline is found within leaf cells. The spatial idioblasts and laticifers. separation of these two MIAs provides a biological explanation Carborundum abrasion has been used as a unique and com- for the low levels of dimeric anticancer drugs found in the plant plementary approach to obtain epidermis-enriched leaf extracts that result in their high cost of commercial production. The ability to measure alkaloid metabolites, enzyme activity, and gene ex- of catharanthine to inhibit the growth of fungal zoospores at pression levels (14, 15). RNA analysis through random sequenc- physiological concentrations found on the leaf surface of Cathar- ing of the leaf epidermis has shown that this single layer of cells is anthus leaves, as well as its insect toxicity, provide an additional biochemically rich in a variety of biosynthetic pathways that in- biological role for its secretion. We anticipate that this discovery clude those for flavonoid, very long chain fatty acids, pentacyclic will trigger a broad search for plants that secrete alkaloids, the triterpenes, and monoterpenoid indole alkaloids (MIAs), re- biological mechanisms involved in their secretion to the plant sur- spectively (13). This biosynthetic diversity in a single cell type face, and the ecological roles played by them. coincides with uncharacterized mechanisms that deliver lipids and triterpenes to the leaf surface to form the cuticle that seals catharanthine | Catharanthus roseus | surface secretion | vindoline the plant surface (16) and advanced alkaloid precursors to spe- cialized leaf mesophyl idioblasts and laticifers (8, 13, 14) for he vinca alkaloids are a well known source of drugs derived elaboration into vindoline. The present study shows that direc- Tfrom the Madagascar periwinkle (Catharanthus roseus). The tional transport mechanisms are coupled to alkaloid biosynthesis four major vinca alkaloids used in various cancer chemotherapies in the leaf epidermis to allow secretion of catharanthine into the are vinblastine, vincristine (or semisynthetic derivatives), vinde- surface wax while vindoline accumulates within specialized idio- PLANT BIOLOGY sine, and vinorelbine (Fig. S1A). In addition, clinical trials are blast/laticifer cells in the leaf. This spatial separation of MIAs fl continuing with new semisynthetic derivatives such as vin unine provides a clear explanation for the low levels of dimeric anti- (Fig. S1A) that may have improved biological properties and may cancer alkaloids found in Catharanthus plants. be effective in a broader range of cancers. Although remarkable efforts by chemists have yielded the total synthesis of dimeric Results alkaloids (1–5), they or their monomeric precursors, catharan- Waxy Surface of C. roseus Contains the Complement of Leaf fi thine and vindoline, are still harvested and puri ed from peri- Catharanthine but Not Vindoline. Dipping of leaves in chloroform winkle plants (Fig. S1B), and the process of alkaloid extraction and has been used to remove surface waxes from plant tissues (16) as purification produces low yields at very high cost. well as other hydrophobic surface chemicals such as the penta- The complexity of the vinca alkaloids is also matched by the cyclic triterpene ursolic acid that accumulates only on the surface multistep pathway involved in their assembly. This pathway re- of Catharanthus leaves (13). Analysis of chloroform soluble quires tryptamine and the monoterpene secologanin for alkaloid chemicals also showed that catharanthine occurs exclusively on assembly, and the pathway is highly regulated by development-, the surface of these leaves (Fig. 1A). Remarkably, only 2% to 5% environment-, organ-, and cell-specific controls (6) that are poorly understood. Although biosynthesis of complex alkaloids such as tabersonine and catharanthine seem to occur within the pro- Author contributions: J.R., V.S., J.M., W.B., and V.D.L. designed research; J.R., V.S., M.W., toderm and cortical cells of Catharanthus root tips (7), the A.M.K.T., and K.P. performed research; W.B. contributed new reagents/analytic tools; J.R., pathway appears to be compartmented in multiple cell types in V.S., M.W., W.B., and V.D.L. analyzed data; and V.D.L. wrote the paper. above-ground organs such as stems, leaves, and flowers (8). The The authors declare no conflict of interest. 2-C-methyl-D-erythritol-4-phosphate pathway, which supplies the This article is a PNAS Direct Submission. carbon skeletons for secologanin biosynthesis (9) as well as ge- 1J.R. and V.S. contributed equally to this work. raniol 10-hydroxylase (G10H) involved in the first committed step 2To whom correspondence should be addressed. E-mail: [email protected]. in this pathway, have been localized to biochemically specialized This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. internal phloem parenchyma (IPAP) cells (10–12). In contrast, 1073/pnas.0911451107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.0911451107 PNAS | August 24, 2010 | vol. 107 | no. 34 | 15287–15292 Downloaded by guest on September 26, 2021 A hydroxylase activity (17). The complement of catharanthine is also Catharanthine found on the surface of this variety when leaves were dipped in e e Vindoline h h t t 100 chloroform (Fig S3A), whereas UPLC analysis of extracts of n o o n e e c c C a a dipped leaf showed that only low levels of vindoline can be found f f A A I I r r % of metabolite on u u M f f M within the leaf (Fig. 1B and Fig. S3B). The decrease in vindoline s s 50 leaf surface f f o o a a Ursolic acid 98± 0.5 content in this mutant line facilitated the detection of vindorosine e e l l % % Catharanthine 99± 1.5 by improving the absorption and mass spectra that could be Vindoline 3.8± 1.8 obtained (Fig. S3C). These results confirm that, although a num- 0.5 1.0 3.0 5.0 30 60 Chlorogenic acid 9.7 ± 5 Chlorophyll 0.033 ±0.012 Time in chloroform (min) ber of alkaloids accumulate within Catharanthus cells (Fig. 1B and Fig. S3B) of these two cultivars, only catharanthine appears to be secreted to the surface. B 224 e c e c e n catharanthine v i a t b a l e l a Rt = 4.45 min r Production of Dimeric MIAs Occurs Only Within Older Catharanthus o s o 282 e s R b m n A e v i t a t i v e A n m Leaves. C. roseus (L.) G. Don cv. Little Delicata leaves of different A n 250 300 350 400 0 8 22 8 0 100 nm ages were analyzed for their levels of catharanthine, vindoline, A 337 e ′ ′ v % and 3 4 -anhydrovinblastine (Fig. 2). Although the concentrations i t a l a l e R e l 0 of vindoline and catharanthine increased with leaf age from leaves e R 500 1000 1500 2000 m/z 1 to 3, these MIAs leveled off and began to diminish from leaves 213 2 4 6 8 10 c e 4 to 9. In all cases, virtually all the catharanthine was in the c e v e n v i 4 b a t b a l a chloroform-soluble fraction whereas all the vindoline appeared r l e R e l m o 252 e R e n 305 vindoline s 0 8 22 8 0 6 b only in extracts of whole leaves (Fig. 2). The accumulation and Rt = 4.55 min A 250 300 350 400 A e v i t i v e nm secretion of catharanthine in the leaf wax exudate of young leaves v 100 i 457 t 1 2 a l e RR ee l a 7 3 strongly suggests that the pathway for catharanthine biosynthesis 5 % is also expressed in the leaf epidermis, as it is for 16-methox- 0 246810 500 1000 1500 2000 ytabersonine (13, 15).
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