Phytochem Rev https://doi.org/10.1007/s11101-021-09768-y (0123456789().,-volV)( 0123456789().,-volV) Alkaloid diversification in the genus Palicourea (Rubiaceae: Palicoureeae) viewed from a (retro-)biogenetic perspective Andreas Berger . Karin Valant-Vetschera . Johann Schinnerl . Lothar Brecker Received: 26 December 2020 / Accepted: 17 July 2021 Ó The Author(s) 2021 Abstract The species-rich genus Palicourea (Rubi- Keywords Palicoureeae Á Alkaloid classification Á aceae: Palicoureeae) is source of an intriguing diver- Biosynthesis Á Chemosystematics Á Chemodiversity sity of alkaloids derived from tryptamine and its precursor tryptophan. So far simple tryptamine ana- Abbreviations logues, polypyrroloindoline, b-carboline, and, most CrSTR Catharanthus roseus strictosidine synthase importantly, monoterpene-indole, i.e., tryptamine-iri- IA Indole alkaloid doid alkaloids of various structural types including INMT Indolethylamine N-methyltransferase javaniside, alstrostine and strictosidine derivatives MIA Monoterpene-indole alkaloid have been identified. Here the diverse alkaloids that OpSTR Ophiorrhiza pumila strictosidine synthase numerous studies have found in the genus are exam- PSR Pictet-Spengler reaction ined and organized according to their structures and RsSTR Rauvolfia serpentina strictosidine synthase biosynthetic groups. Using a parsimony-based SLS Secologanin synthase approach that follows the concept of retro-biogenesis SmGD Strychnos mellodora glucosidase usually applied in synthetic chemistry, possible STR Strictosidine synthase biosynthetic pathways are proposed and important T5H Tryptamine 5-hydroxylase steps and relationships between these alkaloids are TDC Tryptophan decarboxylase highlighted. Understanding alkaloid diversification is SGD Strictosidine ß-glucosidase of importance in studying the ecological significance and evolution of biosynthetic capabilities of the genus Palicourea, and should stimulate future investigations on the biochemical and genetic background. Introduction A. Berger (&) Á K. Valant-Vetschera Á J. Schinnerl Many plant families and genera show an exceptional Department of Botany and Biodiversity Research, diversity of specialized plant metabolites playing University of Vienna, Rennweg 14, A-1030 Vienna, important roles in biotic interactions as well as the Austria adaptation to abiotic factors. This structural diversity e-mail: [email protected] results from a variety of biosynthetic pathway genes L. Brecker (&) and biosynthetic enzymes through coordinated Department of Organic Chemistry, University of Vienna, biosynthesis and metabolic channeling (Jørgensen Wa¨hringer Strasse 38, A-1090 Vienna, Austria et al. 2005; Weng et al. 2012). However, the e-mail: [email protected] 123 Phytochem Rev expression of biosynthetic genes is modulated by inhomogeneous group of compounds since alkaloids environmental factors, and some genes may not be were first described more than two centuries ago expressed for which Lewinsohn and Gijzen (2009) (Meissner 1819). Nowadays, alkaloids are commonly have coined the term ‘‘silent metabolism’’. Knowledge defined as natural products containing one or more about accumulation patterns and biosynthetic rela- nitrogen atoms originating from an amino acid. tionships are among the crucial principles when However, numerous exceptions are known and make studying the ecological importance and evolution of the definition somewhat ambiguous. plant metabolites, and for understanding the use of Due to the lack of such an unambiguous, uniform plants in traditional medicine. Furthermore, they are and generally accepted structural definition, alkaloids essential tools or prerequisites for optimized and are variously and tentatively differentiated based on sustainable production of phytotherapeutics and plant their chemical structure, origin, biogenesis and/or metabolites, and can help to find new leads in drug pharmacological effect. In order to make at least some discovery. Hence, an inventory of specialized plant basic divisions into subgroups, the division in ‘‘pro- metabolites and their classification based upon phylo- toalkaloids’’ and ‘‘true alkaloids’’ — as used by genetic and biosynthetic relationships are of funda- Aniszewski (2015) — is followed here. Being aware mental importance, as exemplified by numerous that the groups are not always unambiguous, the chemotaxonomic studies at the generic level (e.g. nitrogen in ‘‘protoalkaloids’’ is not part of a hetero- Crockett and Robson 2011; Kinoshita 2014; Muan- cycle. In contrast in ‘‘true alkaloids’’ representing the grom et al. 2021; Muellner et al. 2005; Tundis et al. bulk of all known compounds, the amino acid-derived 2014) or at higher-level taxonomic groups (e.g. do nitrogen is located in a heterocycle (e.g. Aniszewski Nascimento Rocha et al. 2015; Jirschitzka et al. 2012; 2015). Wink 2013). One of the largest and structurally most diverse Ideally, the plant group under study is taxonomi- groups of ‘‘true alkaloids’’ are monoterpene-indole cally well settled, its chemical features are known alkaloids (MIA) with way more than 5,100 derivatives from a representative range of taxa, and the biosyn- (Cordell et al. 2001). The group includes countless thetic background is characterized by genetic and important drugs and other bioactive compounds such enzymatic studies. However, the knowledge of as vincristine from Catharanthus roseus L. (Apocy- biosynthetic sequences is at the most limited to single naceae), strychnine from Strychnos spp. (Logani- species or compounds, being mostly of commercial or aceae) or quinine from Cinchona spp. (Rubiaceae) medicinal interest, and then transferred to closely therefore creating a huge impact on human health and related taxa. A possible way to infer biosynthetic society. MIA are formed by a stereospecific stricto- pathways in previously unstudied species is to apply a sidine synthase (STR)-catalyzed Pictet-Spengler reac- parsimony-based approach based on the retro-biosyn- tion (PSR) between the amine function of tryptamine thetic concept, which is usually applied to design and the aldehyde function of secologanin, a seco- multistep enzyme catalyzed transformations. Briefly, iridoid derived from the non-mevalonate terpene retro-biosynthesis starts from a desired target mole- biosynthesis (e.g. Aniszewski 2015; O’Connor and cule and ‘walks’ backwards to known intermediates Maresh 2006). These compounds may thus be classi- and simple precursors using as few and reasonable fied as tryptamine-iridoid alkaloids, a term that reflects (bio-)chemical transformations as possible (see below; their biosynthetic origin better than MIA (see below). Bachmann 2010; Hadadi and Hatzimanikatis 2015). The concept of retro-biosynthesis is presented in more Taxonomy of the genus Palicourea detail in the section ‘‘Biosynthetic classification of Palicourea alkaloids’’. Species of the genus Palicourea (Rubiaceae: Pali- Alkaloids are a structurally diverse and important coureeae) have been reported as rich sources of group of specialized metabolites showing manifold structurally diverse alkaloids indicative of varied biological activities, and more than 21,000 plant- biosynthetic capabilities (e.g. Achenbach et al. 1995; derived compounds have been identified to date Berger et al. 2012, 2015, 2017; Kornpointner et al. (Cordell et al. 2001). There have been a number of 2020; Lopes et al. 2004; Paul et al. 2003). Cyclotides different definitions for this structurally (Koehbach et al. 2013), polyphenols, flavonoids 123 Phytochem Rev (Berger et al. 2016) and iridoids (Berger 2012; Lopes Recent DNA-phylogenetic studies and a re-evaluation et al. 2004) furthermore highlight the chemical of morphological characters have radically challenged diversity of Palicourea species. Whilst each genus the traditional circumscription of Psychotria, the of tribe Palicoureeae appears to have its own charac- largest genus of the alliance, and one of the largest teristic alkaloid content (Berger et al. 2021), a number genera of flowering plants. It was shown that Psycho- of different alkaloid classes were found in Palicourea. tria, in its traditional circumscription, is not mono- It therefore is more diverse than the other genera of the phyletic, and that numerous species once tribe, each of which containing a single class of accommodated in the genus actually belong to other alkaloids. Hence, the genus is a candidate for a more lineages (e.g. Nepokroeff et al. 1999; Razafimandim- in-depth analysis of diversification and possible bison et al. 2014; Robbrecht and Manen 2006). biosynthetic relationships of alkaloids occurring in Consequently, views shifted towards a narrower closely related species. concept of Psychotria and Psychotrieae that peaked The genus Palicourea (Fig. 1) consists of more than in the establishment of the sister tribe Palicoureeae and 800 species and is a member of the speciose Psycho- the transfer of hundreds of species of Psychotria subg. tria alliance comprising the sister tribes Palicoureeae Heteropsychotria to Palicourea (e.g. Berger and Psychotrieae with more than 3,100 species. 2017, 2018; Delprete & Lachenaud 2018; Taylor and Fig. 1 Species of Palicourea show a remarkable morphological (Roem. & Schult.) Borhidi; E: Palicourea padifolia (Humb. & and chemical diversity. A: Palicourea acuminata (Benth.) Bonpl. ex Roem. & Schult.) C.M. Taylor & Lorence; F: Borhidi; B: Palicourea adusta Standl.; C: Palicourea glomeru- Palicourea winkleri Borhidi. Photographs: A. Berger lata (Donn. Sm.) Borhidi; D: Palicourea