2.06 the Natural Products Chemistry of Cyanobacteria Kevin Tidgewell, Benjamin R
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2.06 The Natural Products Chemistry of Cyanobacteria Kevin Tidgewell, Benjamin R. Clark, and William H. Gerwick, University of California San Diego, La Jolla, CA, USA ª 2010 Elsevier Ltd. All rights reserved. 2.06.1 Introduction 142 2.06.2 Trends in the Structures of Cyanobacterial Natural Products 143 2.06.2.1 Taxonomy 143 2.06.2.2 Molecular Weight 144 2.06.2.3 Structural Classes 146 2.06.2.4 Amino Acids 147 2.06.2.5 Other Trends 150 2.06.3 Fatty Acid Derivatives from Cyanobacteria 150 2.06.4 Terpenes 153 2.06.4.1 Tolypodiol 153 2.06.4.2 Noscomin/Comnostins 154 2.06.4.3 Tasihalide 154 2.06.5 Saccharides and Glycosides 154 2.06.5.1 Iminotetrasaccharide 156 2.06.5.2 Cyclodextrin 157 2.06.6 Peptides 158 2.06.6.1 Lyngbyatoxins 159 2.06.6.2 Aeruginosins 159 2.06.6.3 Cyanopeptolins 161 2.06.6.4 Cyclamides 163 2.06.6.5 Anatoxin-a(s) 165 2.06.7 Polyketides 165 2.06.7.1 Biosynthesis of Polyketides 165 2.06.7.2 Oscillatoxin/Aplysiatoxin 166 2.06.7.3 Acutiphycin 166 2.06.7.4 Scytophycin/Tolytoxin/Swinholide 166 2.06.7.5 Nakienone 168 2.06.7.6 Nostocyclophanes 168 2.06.7.7 Caylobolide 168 2.06.7.8 Oscillariolide/Phormidolide 169 2.06.7.9 Borophycin 169 2.06.8 Lipopeptides 169 2.06.8.1 Ketide-Extended Amino Acids (Peptoketides) 169 2.06.8.1.1 Dolastatin 10 169 2.06.8.1.2 Barbamide 171 2.06.8.2 Simple Ketopeptides 171 2.06.8.2.1 Hectochlorin 171 2.06.8.2.2 Antanapeptin A 172 2.06.8.2.3 Makalika ester 173 2.06.8.2.4 Microcystin LR 174 2.06.8.3 Complex Ketopeptides 175 2.06.8.3.1 Jamaicamide A 175 2.06.8.3.2 Mirabimide E 176 2.06.8.3.3 Madangolide 178 2.06.8.3.4 Kalkitoxin 178 2.06.8.3.5 Microcolin 178 141 142 The Natural Products Chemistry of Cyanobacteria 2.06.8.3.6 Apratoxin 179 2.06.8.3.7 Ypaoamide 179 2.06.8.3.8 Curacin A 180 2.06.8.3.9 Malyngamide R 181 2.06.8.3.10 Largazole 181 2.06.9 Conclusion 182 References 183 2.06.1 Introduction Cyanobacteria, also known botanically as Cyanophyta or ‘blue-green algae’, are fascinating organisms because of their abundance and variety, their impact on the ecology of aquatic systems, and their exceptional capacity to produce structurally diverse and highly bioactive secondary metabolites. This exceptional capacity has raised both popular and scientific interests in these organisms as they contribute to toxicity events, both in marine and freshwater environments, and their capacity to yield lead molecules for drug discovery efforts. Much of the recognition of this biosynthetic talent of cyanobacteria owes to the 30-year effort of Richard E. Moore who pioneered the investigation of marine blue-green algae beginning in 1977 with the discovery of majusculamides A and B.1 However, freshwater species were reported in the scientific literature as early as the 1930s to produce toxins that negatively impacted human as well as animal health.2 As a result, both marine and freshwater cyanobacteria have been actively pursued for their unique and bioactive components; however, the motivations have differed with most marine investigations looking for ‘remedies’ whereas freshwater ones have focused on the ‘risks’.3 Because of this considerable interest, the natural products chemistry of cyanobacteria has been relatively frequently and thoroughly reviewed. In addition, the natural products of marine cyanobacteria are reviewed yearly in the long-standing comprehensive review of marine natural products.4 For example, more than 200 reviews of the search terms ‘cyanobacteria toxin review’ are retrieved in SciFinder with most of these focusing on freshwater species. Of marine reviews on cyanobacteria, something less than 50 exist; however, several have occurred recently and provided comprehensive, insightful, and broad coverage of their chemistry,5–9 biological properties,10–15 and biosynthetic pathways.16,17 Hence, in constructing this perspective review of the natural products chemistry of cyanobacteria, we have attempted to dissect, analyze, and make understandable the metabolites of these gifted organisms by applying a biosynthetic reasoning to their presentation. We have accessed the natural products of marine, freshwater, and terrestrial cyanobacteria by considering diverse sources of information, including proprietary databases such as MarinLit and SciFinder, the various literature reviews described above in this introduction, and our personal knowledge of the field. We begin the chapter with a detailed analysis of the sources of reported cyanobacterial secondary metabolites at the genus level, and for the more prolific genera, the species level as well. Since the marine natural products literature is readily accessed through the MarinLit database program, we have analyzed the molecular weight ranges of the described marine cyanobacterial metabolites. Next, we have analyzed the types of metabolites that have been isolated from these life-forms in terms of their structural classes and major modifications. We also looked in some detail as to the types of amino acids that are used by cyanobacteria in producing their natural products and have produced a series of figures that details these findings. These charts are accompanied by a discussion of the trends in secondary metabolism by cyanobacteria and give some insights that are followed up by examples in the ensuing discussion of specific compounds. The section of the chapter describing examples of specific cyanobacterial metabolites begins with a description of the fatty acid-derived compounds, which generally lack recognizable amino acid components and follow this with those possessing a terpene-deriving section. This theme of primarily carbon-based frameworks is continued in the next section of metabolites, which are derived exclusively from polyketide biosynthetic pathways. Metabolites of a pure peptide origin are presented next; however, there are substances that are both alkaloidal and of pure peptide origin (e.g., a number of cyanobacterial peptides possess an N,N-dimethylvalyl terminus). The Natural Products Chemistry of Cyanobacteria 143 Next, peptides and polyketides are joined to several classes of lipopeptide metabolites, and this constitutes a major biosynthetic theme in cyanobacteria. Indeed, cyanobacterial lipopeptides come in two distinctive categories: polyketide sections which transition into a nonribosomal peptide synthetase (NRPS) section, thus forming amide or in some cases ester bonds (e.g., with -hydroxy acids), and the reverse wherein the carboxyl function of an amino acid serves as the starter unit for one or more polyketide extensions. These are fundamental and significant biosynthetic variants, and hence, are a good basis for further dissection of cyanobacterial lipopeptides. As such, new terminology is herein presented so as to facilitate the discussion of these two classes; polyketides transitioning to peptides are described as ‘ketopeptides’ (e.g., 79–84, 93), whereas the reverse, peptides modified by polyketide extension, are to be known as ‘peptoketides’ (e.g., 1); in each case, the root word order describes the biosynthetic sequence. However, cyanobacterial natural products often possess elements of both of these two motifs, occurring either as polyketide synthetase PKS–NRPS–PKS or NRPS–PKS–NRPS constructs; because further new terminology seems cumbersome, these will be described simply as ‘complex ketopeptides’ or ‘complex peptoketides’. 2.06.2 Trends in the Structures of Cyanobacterial Natural Products 2.06.2.1 Taxonomy The order Oscillatoriales accounts for 58% of all isolated secondary metabolites from marine cyanobacterial sources while the Nostocales accounts for 24%, Chroococcales 10%, Stigonematales 8%, and Pleurocapsales <1%. Hence, a majority of the unique natural products of cyanobacteria are derived from filamentous forms with generally larger genome sizes (6.0–10 Mbp) than the unicellular forms (1.7–4.0 Mbp), and this matches the deduced capacity to produce natural products from genome sequence information (Figure 1).18 The genus that has yielded the most reported structures is Lyngbya, accounting for 35% of all cyanobacterial secondary metabolites. Other genera with significant contributions are Nostoc (11%), Oscillatoria (9%), Microcystis (7%), and Schizothrix (6%). Genera with smaller contributions are Anabaena (4%), Hapalosiphon (4%), Tolypothrix (4%), Symploca (3%), Phormidium (2%), Kyrtuthrix (2%), Scytonema (2%), and Synechocystis (2%). The remaining 9% of compounds come from 23 different genera (Figure 2). Microcystis aeruginosa (order Chroococcales) accounts for 92% of the compounds isolated from the genus Microcystis (49 compounds total) with 6% coming from Microcystis viridis and 2% from undetermined species. However, it is likely that some variants of the microcystin structure were not tallied in our analysis. Nostocales 24% Oscillatoriales Chroococcales 58% 10% Stigonematales 8% Pleurocapsales 0% Figure 1 Percentage of isolated marine cyanobacterial natural products by taxonomic order. (n ¼ 678) 144 The Natural Products Chemistry of Cyanobacteria Plectonema Prochlorothrix Raphidiopsis Scytonema Stigonema Oscillatoria Phormidium 2% 1% 2% Rivularia 9% 1% Symploca 3% Nostoc Schizothrix 11% 6% Synechococcus Synechocystis Nodularia 2% 1% Tolypothrix 4% Microcystis 7% Trichodesmium Westiellopsis Microcoleus Westiella 1% Anabaena 4% Aphanizomenon 1% Aphanocapsa Aulosira Calothrix Chroococcus Chlorogloeopsis Cylindrospermopsis Lyngbya 35% Kyrtuthrix Geitlerinema Cylindrospermum 2% Fischerella Hyella Hapalosiphon 1% Hormothamnion 4% Figure 2 Percentage of isolated marine cyanobacterial natural products by genus. (n ¼ 678) Compounds isolated from the genus Nostoc (order Nostocales, 73 compounds) have predominantly been isolated from unknown species (91%). Nostoc commune accounts for only 6% of the isolated compounds with Nostoc linckia, Nostoc muscorum, and Nostoc spongiaeforme, each responsible for about 1%. The genus Oscillatoria (order Oscillatoriales, 64 compounds total) has a much broader distribution of isolated compounds among different species as compared to the other genera of cyanobacteria; 30% comes from undetermined species, 28% from Oscillatoria agardhii, 19% from Oscillatoria nigroviridis, and 13% from Oscillatoria spongelia.