Molluscan Biological and Chemical Diversity: Secondary Metabolites and Medicinal Resources Produced by Marine Molluscs
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Biol. Rev. (2010), pp. 000–000. 1 doi: 10.1111/j.1469-185X.2010.00124.x Molluscan biological and chemical diversity: secondary metabolites and medicinal resources produced by marine molluscs Kirsten Benkendorff∗ School of Biological Sciences, Flinders University, GPO Box 2100 Adeliade, 5001, SA, Australia (Received 4 March 2009; revised 10 December 2009; accepted 17 December 2009) ABSTRACT The phylum Mollusca represents an enormous diversity of species with eight distinct classes. This review provides a taxonomic breakdown of the published research on marine molluscan natural products and the medicinal products currently derived from molluscs, in order to identify priority targets and strategies for future research. Some marine gastropods and bivalves have been of great interest to natural products chemists, yielding a diversity of chemical classes and several drug leads currently in clinical trials. Molluscs also feature prominently in a broad range of traditional natural medicines, although the active ingredients in the taxa involved are typically unknown. Overall secondary metabolites have only been investigated from a tiny proportion (<1%) of molluscan species. At the class level, the number of species subject to chemical studies mirrors species richness and our relative knowledge of the biology of different taxa. The majority of molluscan natural products research is focused within one of the major groups of gastropods, the opisthobranchs (a subgroup of Heterobranchia), which are primarily comprised of soft-bodied marine molluscs. Conversely, most molluscan medicines are derived from shelled gastropods and bivalves. The complete disregard for several minor classes of molluscs is unjustified based on their evolutionary history and unique life styles, which may have led to novel pathways for secondary metabolism. The Polyplacophora, in particular, have been identified as worthy of future investigation given their use in traditional South African medicines and their abundance in littoral ecosystems. As bioactive compounds are not always constitutively expressed in molluscs, future research should be targeted towards biosynthetic organs and inducible defence reactions for specific medicinal applications. Given the lack of an acquired immune system, the use of bioactive secondary metabolites is likely to be ubiquitous throughout the Mollusca and broadening the search field may uncover interesting novel chemistry. Key words: bioactivity, biodiversity, chemical defence, molluscan evolution, marine natural products, natural remedies, secondary metabolism, traditional medicine. CONTENTS I. Introduction ................................................................................................ 2 (1) Molluscan biological diversity .......................................................................... 2 (2) Molluscan chemical diversity ........................................................................... 4 II. Taxonomic Distribution of Molluscan Metabolites ......................................................... 6 (1) Minor classes ........................................................................................... 6 (2) Cephalopoda ........................................................................................... 8 (3) Bivalvia ................................................................................................. 10 (4) Gastropoda ............................................................................................. 10 (a) Eogastropoda and non-heterobranch orthogastropods ............................................. 10 (b) Heterobranch gastropods ........................................................................... 11 * Address for correspondence: Tel: +61 8 8201 3959; Fax: +61 8 8201 3015; Email: Kirsten.benkendorff@flinders.edu.au Biological Reviews (2010) 000–000 © 2010 The Author. Journal compilation © 2010 Cambridge Philosophical Society 2 Kirsten Benkendorff III. Molluscan Medicines ....................................................................................... 12 IV. Conclusions ................................................................................................ 15 V. Acknowledgements ......................................................................................... 15 VI. References .................................................................................................. 15 I. INTRODUCTION et al., 2002; Cummins et al., 2006), predatory behaviour (e.g. Roseghini et al., 1996; Craig, 2000; Kanda et al., 2003) and Throughout history, molluscs have provided a wide range of defensive secretions (e.g. Ireland & Faulkner, 1978; Pawlik, human resources, including food, shells, dyes and medicines Albizati & Faulkner, 1986; Marin et al., 1999; Kelly et al., (e.g. Fig. 1). In many cultures shelled gastropods and bivalves 2003; Derby et al., 2007). Consequently, there should be are regarded as a delicacy or healthy food and they also much scope for future drug discovery within this phylum. feature in a range of traditional natural remedies (e.g. Hu, The continual discovery of novel drug leads from the 1980; Herbert et al., 2003; Prabhakar & Roy, 2009). In most enormous pool of available species requires a strategic cases there has been no scientific research undertaken to approach, such as the investigation of traditional medicines substantiate the health benefits of molluscs. However, there and/or previously unstudied sources that are likely to is increasing interest in the bioactivity of mollusc extracts have independently evolved novel pathways for secondary and secondary metabolites (see Cimino & Gavagnin, 2006). metabolism. As outlined by Cimino & Ghiselin (2001) Currently, natural products isolated from molluscs and their chemical defence appears to have evolved differently structural analogues are particularly well represented in the in different types of organisms. Consequently, it could anticancer compounds in clinical trials (Simmons et al., 2005). be predicted that distinct chemical structures will occur Nevertheless, it is presently unclear whether the production within molluscan groups that have evolved under different of bioactive secondary metabolites is ubiquitous within the environmental and biological pressures. The purpose of this Phylum Mollusca. review is to examine the current literature on molluscan The term mollusc is derived from the Latin word molluscus secondary metabolites to identify major gaps in our meaning ‘soft’. Despite the presence of a shell in some knowledge of molluscan chemistry. Combined with an molluscan groups, all molluscs are essentially soft-bodied, assessment of molluscan evolution and medicinal resources, making them vulnerable to predators and pathogens. Even this could help refine future targets for natural products those with a shell must regularly open the shell, or extend research. The approach used here primarily involves a their muscular foot beyond it, for the purposes of feeding taxonomic classification of molluscan secondary metabolites and locomotion. Thus the shell does not present a true to highlight under-represented taxa. The bias towards certain physical barrier to microbial infection. However, molluscs taxa is also compared to the distribution of species used in often live in microbially rich habitats, such as soil and medicinal remedies, to establish further limitations in our leaf litter on land and amongst marine benthic sediments knowledge on bioactive compounds from molluscs. and hard reef communities. The majority of molluscan diversity occurs in the sea, where even in the water (1) Molluscan biological diversity column there is an estimated 105 –106 microbial cells ml−1 (Whitman, Coleman & Wiebe, 1998). When any natural Molluscs are the second largest animal phylum on earth, or artificial surface is placed in the marine environment, constituting approximately 7% of living animals. There bacteria rapidly settle, attach and form biofilms (Davis et al., are currently around 52,000 named species of marine 1989), which can facilitate pathogenic invasion. However, molluscs (Bouchet, 2006) and an estimated diversity of like all invertebrates, molluscs do not have an acquired 100,000–200,000 species (Pechenik, 2000). Molluscs are immunological memory (Sminia & Van Der Knaap, 1986; relatively well described compared to many other inver- Hooper et al., 2007). This suggests that molluscs must have tebrate phyla and the taxonomy is fairly well resolved evolved alternative defence strategies to protect themselves for an enormous diversity of species from many regions against the onslaught of microbial invasion. Indeed, their around the world, despite some remaining unresolved innate immune system does appear to have a well-developed phylogenetic disputes (e.g. Haszprunar, 1996; Ponder & humoral component with the biosynthesis of antimicrobial Lindberg, 1997; Colgan, Ponder & Eggler, 2000; reviewed defence factors (e.g. Tripp, 1975; Mitta et al., 2000b; Mitta, by Ponder & Lindberg, 2008). Molluscs are diverse not Vandenbulcke & Roch, 2000; Cellura et al., 2007; Li, Zhao only in terms of their species richness, but also encom- & Song, 2009). Under the pressure of natural selection, pass a wide range of morphologies and ecological niches. a range of different antibacterial, antifungal, antiparasitic Their habitats range from the highest alpine regions to and antiviral secondary metabolites may have evolved in the deepest sea vents and they have adapted to a range molluscs, for circulation in