Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae Rønsted, Nina; Symonds, Matthew R. E.; Birkholm, Trine; Christensen, Søren Brøgger; Meerow, Alan W.; Schmidt, Marianne Molander; Mølgaard, Per; Petersen, Gitte; Rasmussen, Nina; van Staden, Johannes; Stafford, Gary Ivan; Jäger, Anna Published in: BMC Evolutionary Biology DOI: 10.1186/1471-2148-12-182 Publication date: 2012 Document version Publisher's PDF, also known as Version of record Document license: CC BY Citation for published version (APA): Rønsted, N., Symonds, M. R. E., Birkholm, T., Christensen, S. B., Meerow, A. W., Schmidt, M. M., Mølgaard, P., Petersen, G., Rasmussen, N., van Staden, J., Stafford, G. I., & Jäger, A. (2012). Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of Amaryllidaceae. BMC Evolutionary Biology, 12, [182]. https://doi.org/10.1186/1471-2148-12-182 Download date: 29. Sep. 2021 Rønsted et al. BMC Evolutionary Biology 2012, 12:182 http://www.biomedcentral.com/1471-2148/12/182 RESEARCH ARTICLE Open Access Can phylogeny predict chemical diversity and potential medicinal activity of plants? A case study of amaryllidaceae Nina Rønsted1*, Matthew R E Symonds3, Trine Birkholm2, Søren Brøgger Christensen2, Alan W Meerow4,5, Marianne Molander2, Per Mølgaard2, Gitte Petersen1, Nina Rasmussen2, Johannes van Staden6, Gary I Stafford1 and Anna K Jäger2 Abstract Background: During evolution, plants and other organisms have developed a diversity of chemical defences, leading to the evolution of various groups of specialized metabolites selected for their endogenous biological function. A correlation between phylogeny and biosynthetic pathways could offer a predictive approach enabling more efficient selection of plants for the development of traditional medicine and lead discovery. However, this relationship has rarely been rigorously tested and the potential predictive power is consequently unknown. Results: We produced a phylogenetic hypothesis for the medicinally important plant subfamily Amaryllidoideae (Amaryllidaceae) based on parsimony and Bayesian analysis of nuclear, plastid, and mitochondrial DNA sequences of over 100 species. We tested if alkaloid diversity and activity in bioassays related to the central nervous system are significantly correlated with phylogeny and found evidence for a significant phylogenetic signal in these traits, although the effect is not strong. Conclusions: Several genera are non-monophyletic emphasizing the importance of using phylogeny for interpretation of character distribution. Alkaloid diversity and in vitro inhibition of acetylcholinesterase (AChE) and binding to the serotonin reuptake transporter (SERT) are significantly correlated with phylogeny. This has implications for the use of phylogenies to interpret chemical evolution and biosynthetic pathways, to select candidate taxa for lead discovery, and to make recommendations for policies regarding traditional use and conservation priorities. Keywords: Amaryllidaceae, Phylogeny, Chemical diversity, Prediction, Lead discovery Background [6,11-15], defence against herbivores [16,17], more effi- During evolution, plants and other organisms have devel- cient selection of plants for the development of traditional oped a diversity of chemical defence lines, leading to the medicine and lead discovery [18-22] as well as inform con- evolution of various groups of specialized metabolites servation priorities [23]. such as alkaloids, terpenoids, and phenolics, selected for Several studies have confirmed the usefulness of specia- their endogenous biological function [1-7]. Intuitively, a lized metabolites such as glucosinolates, iridoids, sesqui- correlation between phylogeny and biosynthetic pathways terpene lactones, flavonoids, and phenolics to support is sometimes assumed [1,8-10] and could offer a predictive molecular based phylogenies contradicting morphologic approach enabling deduction of biosynthetic pathways patterns [11,12,24-29]. On the contrary, several studies have found inconsistency of specialized metabolite profiles * Correspondence: [email protected] at various taxonomic levels and indicated that specialized 1Botanic Garden, Natural History Museum of Denmark, Sølvgade 83, Opg. S, Copenhagen DK-1307, Denmark Full list of author information is available at the end of the article © 2012 Rønsted et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Rønsted et al. BMC Evolutionary Biology 2012, 12:182 Page 2 of 12 http://www.biomedcentral.com/1471-2148/12/182 chemistry and anti-herbivore defence syndromes tend to subfamily Amaryllidoideae as a model system for testing be poorly correlated with plant phylogeny [6,7,13,30]. the correlation between phylogenetic and chemical di- Lack of congruence between specialized chemistry and versity and biological activity. phylogeny may be caused by several different phenom- Amaryllidaceae subfamily Amaryllidoideae sensu APG III ena. One contributing factor is convergent evolution by [40] (formerly recognized as a separate family, Amaryllida- which the same or similar traits originate independently ceae J.St.-Hil.) is a widely distributed subfamily of 59 genera in taxa that are not necessarily closely related, often in and about 850 species. Amaryllidoideae has centres of di- response to similar environmental challenges [17,31]. A versity in South Africa, South America, particularly in the striking example of convergent evolution is the common Andean region, and in the Mediterranean, three of the use of the sex pheromone (Z)-7-dodecen-l-yl acetate by recognized hotspots of biodiversity on Earth [41,42] (www. over 120 species of primarily Lepidopteran insects and biodiversityhotspots.org). Plants of the Amaryllidoideae are female Asian elephants, Elephas maximus [32]. In rela- used in traditional medicine to treat mental problems, pri- tion to plants, well known convergent morphological marily in Southern Africa [43,44]. The traditional use of adaptations are the occurrence of prickles, thorns, and plants of Amaryllidoideae has been related to their unique spines, which have evolved to avoid or limit herbivory and subfamily specific alkaloid chemistry (Figure 1). Over [33], succulence as adaptation to dry environments in 500 alkaloids have been described from various species and both North American Cactaceae and African Euphorbia have been subdivided into 18 major types based on hypo- [34,35], and insectivorous plants, which have evolved thetical biosynthetic pathways [45-47]. Extracts or isolated several times in response to a nitrogen-deficient envir- alkaloids of Amaryllidaceae species have shown activity onment [36]. Likewise, chemical defence lines may also in vitro in a range of assays related to disorders of the cen- have arisen independently in unrelated taxa, and conver- tral nervous system, primarily Alzheimers disease (inhib- gent evolution in plant specialized metabolism appears ition of acetylcholinesterase, AChE) [21,48-51], and anxiety to be surprisingly common [6,17,31,37]. For example, and depression (affinity to the serotonin re-uptake trans- the ability to produce cyanogenic glycosides appears to porter, SERT) [21,52,53]. Galanthamine is registered in a have evolved independently in many different plant fam- number of countries as an AChE inhibitor (Reminyl or ilies [17,31]. Rezadyne; Janssen Pharmaceutica) [54]. Another Amarylli- However, convergent evolution can be difficult to ver- daceous alkaloid, sanguinine (9-O-demethylgalanthamine), ify because absence of evidence is not evidence of ab- is shown to be a ten times more potent inhibitor of AChE sence and it is possible that some compounds presently than galanthamine in vitro [55]. considered to be limited to some lineages are indeed Amaryllidaceae subfamily Amaryllidoideae is therefore more universally found in plants [31]. Specialized com- an ideal model system for comparing phylogenetic and pounds are not continuously expressed, but may be pro- chemical diversity with bioactivity. Previous molecular duced as a response to herbivory or other damage, the phylogenetic studies based on plastid gene regions (rbcL, expression may also be dependent on the environment trnLF, and ndhF) have confirmed Amaryllidoideae as [38] and plants often use a combination of several defen- monophyletic and resolved many taxa into geographic- sive traits [7,17]. In addition, chemosystematic data are ally confined monophyletic groups [42,56]. The African scattered in the literature and negative results are often tribe Amaryllideae has been well supported as sister not reported. Absence or presence of a compound is also group to the remaining taxa. However, the relationship dependent on the amount of plant material investigated among several other early diverging lineages, in particu- as well as the detection limit of the analytical methods lar the African tribes Haemantheae and Cyrtantheae, [27,39]. Finally, the existence of several different phyto- and the Australasian Calostemmateae are not well sup- chemical methods can cause inconsistence in the results ported by previous studies and remain problematic [42]. reported in the literature. In a study by Meerow and Snijman [42] based on parsi- Nevertheless,