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Chemistry and Biology of Monoterpene Indole Alkaloid Biosynthesis

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Chemistry and Biology of Monoterpene Indole Alkaloid Biosynthesis REVIEW www.rsc.org/npr | Natural Product Reports Chemistry and biology of monoterpene indole alkaloid biosynthesis Sarah E. O’Connor* and Justin J. Maresh Received (in Cambridge, UK) 6th September 2005 First published as an Advance Article on the web 26th May 2006 DOI: 10.1039/b512615k Covering: up to 2006 Monoterpene indole alkaloids exhibit a diverse array of structures and biological activities. The biosynthetic pathways for several representative terpene indole alkaloids are described in detail. 1 Introduction 1 Introduction 2 Biosynthesis of terpene indole alkaloids 2.1 Rauwolfia serpentina The terpene indole alkaloids are a diverse class of natural products, 2.1.1 Sarpagan and ajmalan type: ajmaline comprising over 2000 members. These complex natural products 2.1.2 Yohimbine possess a range of chemical structures and a wealth of biological 1,2 2.2 Catharanthus roseus activities (Fig. 1). Terpene indole alkaloids are used as anti- 3 2.2.1 Corynanthe type: ajmalicine, tetrahydroalsonine and cancer, anti-malarial and anti-arrhythmic agents (Fig. 1). The serpentine biosynthetic pathways of some classes of terpene indole alkaloids 2.2.2 Strychnos, aspidosperma, and iboga type: are well understood. In certain cases, many of the enzymes that are preakuammicine, vindoline, catharanthine responsible for biosynthesis have been cloned and mechanistically 2.2.3 Bisindole type: vinblastine studied in vitro. In other cases, the biosynthetic pathway is only 2.3 Ophiorrhiza pumila, Camptotheca acuminata proposed based on the results of feeding studies with isotopically 2.3.1 Quinoline type: camptothecin labeled substrates and from the structures of isolated biosynthetic 2.4 Cinchona intermediates. 2.4.1 Quinoline type: quinine Early studies of plant alkaloid biosynthesis relied on adminis- 3 Localization of terpene indole alkaloid biosynthetic tration of isotopically labeled starting materials to differentiated enzymes plants or plant cell cultures, followed by isolation and structural 4 Conclusion characterization of the labeled products. Additionally, chemi- 5 References cal reactions with isolated biosynthetic intermediates allowed predictions of chemically reasonable transformations. However, with recent advances in molecular biology, the biosynthetic Department of Chemistry, Massachusetts Institute of Technology, Building 18-592, 77 Massachusetts Avenue, Cambridge, MA 02139-4307, USA. pathways of plant alkaloid natural products have been subject to E-mail: [email protected]; Fax: +1 (617) 324 0505; Tel: +1 (617) 324 0180 study at the enzymatic level.4,5 A number of enzymes involved Sarah O’Connor received her BS in chemistry from the University of Chicago and a PhD in organic chemistry from MIT and Caltech with Professor Barbara Imperiali. She held a postdoctoral appointment as an Irving Sigal postdoctoral fellow at Harvard Medical School with Professor Christopher T. Walsh. She is currently an assistant professor in the chemistry department at MIT. Her research interests include understanding natural product biosynthetic pathways and enzyme mechanisms. Justin Maresh earned a PhD in organic chemistry from the University of Chicago (2004), where he worked under the guidance of Professor David Lynn. His research interests include the mechanisms of enzymes involved in alkaloid biosynthesis. Sarah E. O’Connor Justin J. Maresh 532 | Nat. Prod. Rep., 2006, 23, 532–547 This journal is © The Royal Society of Chemistry 2006 in plant alkaloid biosynthesis have been successfully cloned, and many more enzymes have been purified from alkaloid producing plants or cell lines.6 Plant biosynthetic pathways are much less well understood than prokaryotic metabolic pathways since the genes expressing complete plant pathways are usually not clustered. The study of plant-derived secondary metabolites typically requires that each plant enzyme of a pathway be individually isolated and cloned independently of one another. Many plant enzymes have been characterized by “reverse genetics” in which the enzymes are isolated from plants or plant cell culture by traditional biochemical chromatography techniques.6 After purification, the protein may be partially sequenced, and this sequence information is then used to identify the corresponding gene from a plant cDNA library.More recently, plant cDNA libraries have been successfully screened for well known classes of enzymes such as P450 enzymes or acetyl transferase homologues.7,8 However, this homology- based cloning method is limited to identification of enzymes with regions of high sequence conservation. Alternatively, plant cell lines can be stimulated with an elicitor to produce alkaloids. Genes that are upregulated in the elicited strain are likely to be involved in alkaloid biosynthesis.9,10 In this review we highlight a few well characterized alkaloid biosynthetic pathways for representative members of the terpene indole alkaloid family. Specifically, we discuss the biosynthetic pathways of the corynanthe group (ajmalicine, serpentine, yohim- bine), the iboga group (catharanthine), the aspidosperma group (tabersonine, vindoline), and the quinoline group (camptothecin, quinine). 2 Biosynthesis of terpene indole alkaloids All terpene indole alkaloids are derived from tryptophan and the iridoid terpene secologanin (Scheme 1). Tryptophan decarboxy- lase, a pyridoxal dependent enzyme,11–13 converts tryptophan to tryptamine.14 The involvement of an iridoid monoterpene in these indole alkaloid pathways was first proposed after the structures Fig. 1 Representative terpene indole alkaloids, with corresponding of several iridoid terpenes were elucidated.15–17 Secologanin was biological function and species of plants from which they are isolated. subsequently identified as the specific iridoid precursor.18–20 Scheme 1 First steps of terpene indole alkaloid biosynthesis. This journal is © The Royal Society of Chemistry 2006 Nat. Prod. Rep., 2006, 23, 532–547 | 533 Secologanin is itself a natural product, and the biosynthetic secologanin,34 may be the rate-limiting step in indole alkaloid pathway for this molecule has not been fully elucidated. Isopen- biosynthesis. Therefore, overexpression of secologanin synthase tenyl diphosphate (IPP), the precursor for all terpenoids, is (SLS) in alkaloid-producing plants could potentially improve the produced by either the mevalonate biosynthetic pathway or the yield of secologanin-derived alkaloids. more recently discovered triose phosphate/pyruvate pathway.21 Tryptamine and secologanin are utilized in the first committed Feeding studies with Catharanthus roseus cell suspension cultures step of terpene indole alkaloid biosynthesis. In this step, the and 13C-glucose strongly suggest that secologanin is ultimately enzyme strictosidine synthase catalyzes a stereoselective Pictet– derived from the triose phosphate/pyruvate or “non-mevalonate” Spengler condensation35,36 between tryptamine and secologanin pathway (Scheme 2).22 Feeding studies with cultures of Ophi- to yield strictosidine (iso-vincoside) (S stereochemistry at C5, orrhiza pumila were also consistent with the utilization of the Scheme 1).37–42 non-mevalonate pathway in secologanin biosynthesis.23 Several Strictosidine synthase43 has been isolated and cloned from enzymes involved in the biosynthesis of IPP-DXP synthase, DXP the plants Catharanthus roseus,44–49 Rauwolfia serpentina,50–57 and, reductoisomerase, and MEP synthase have been cloned from recently, O. pumila.58 A crystal structure of strictosidine synthase Catharanthus roseus.24,25 In the first committed step of iridoid from R. serpentina has recently been reported.59 Notably, a terpene biosynthesis, geraniol, derived from IPP, is hydroxylated second “Pictet–Spenglerase”, norcoclaurine synthase (involved by geraniol-10-hydroxylase. Geraniol-10-hydroxylase (G10H) has in tetrahydroisoquinoline biosynthesis in Thalictrum flavum), has been heterologously expressed in yeast and shown to hydroxy- dramatically different substrate specificity and shows no sequence late geraniol in vitro.26,27 Feeding experiments with 3H-labeled homology to strictosidine synthase.60 terpene intermediates suggest that 10-hydroxygeraniol, iridodial Strictosidine synthase tolerates a variety of substitutions on the and iridotrial are intermediates in the secologanin biosynthetic indole ring of tryptophan, as well as benzofuran and benzoth- pathway (Scheme 2).28,29 Oxidation of the iridotrial aldehyde to iophene heterocycles.61 However, tryptophan, phenyethylamine, the carboxylic acid is followed by esterification and glucosylation and pyrrole derivatives are not accepted. Although strictosidine to yield deoxyloganin; subsequent hydroxylation of deoxyloganin synthase does not accept other naturally occurring iridoid aldehy- yields loganin. Secologanin is then generated by oxidative cleavage des, the enzyme does accept certain semi-synthetic derivatives of of loganin by the enzyme secologanin synthase (SLS). This secologanin (Fig. 2).51,61,62 NADPH dependent P450 oxidase was isolated from a cDNA The Apocynaceae, Loganiaceae, Rubiaceae and Nyssaceae library of an alkaloid producing C. roseus cell culture,30 and was families of plants each produce terpene indole alkaloids with shown to convert loganin to secologanin in vitro, presumably dramatically diverse structures (Fig. 3). The mechanisms and through a radical mediated reaction mechanism.31 Recent data control of the processes by which strictosidine rearranges into from precursor feeding studies suggest that the biosynthesis these diverse families of
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