Chemical and physical properties of functional metabolites

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Introduction

Chemists typically classify these compounds according to their biogenetic origin in isoprenoids, polyketides, amino acids and peptides, shikimate derivatives and carbohydrates. Furthermore, there are many other classes of compounds derived by mixed biosynthesis arising from combinations of the above pathways. Over half of the metabolites described to date (56%) are derived from the isoprenoid pathway, with the remainder split mainly between the amino acid (20%) and polyketide (20%) pathways. Interestingly, the nucleic acid and carbohydrate pathways constitute only 1% of the metabolic pathways compared to the important role that these classes of compounds play in primary metabolism.

The pathways leading to the synthesis of these compounds are often complex and significant quantities of metabolic energy may be expended to generate compounds that could otherwise have been directed to growth or reproduction. Hence it is believed that the cost for their production must be compensated for by an ecological (related to outer interactions) or physiological (related to inner processes) benefit to the producing organism.

Isoprenoids

What makes isoprenoids, including terpenes and steroids, so unique is the incredible chemistry that nature uses to produce these compounds. The immense variety of terpenes identified to date, are derived largely from three biosynthetically related, yet simple-looking precursors (Figure 1). These precursors, GPP, FPP, and GGPP, are essentially polymers of two, three, or four isoprene groups (5-carbon alkene units) covalently tethered together and punctuated by a terminal diphosphate group. The magic begins when one starts to gaze at the amazing number of structural derivatives that can arise from each of these precursors and then considers how this diversity might arise by the action of a single biosynthetic step catalyzed by terpene synthases or terpene cyclases. The large majority of known terpenes derive from terrestrial sources, mainly plants and fungi. On the contrary, marine terpenes are scarcely studied and their systematic investigation started only two or three decades ago. In analogy with their terrestrial counterparts, the number and diversity of marine terpenes are steadily increasing, even if our knowledge of the biochemical processes underlying their synthesis is very limited. In fact, few enzymes (terpene cyclases) responsible for the cyclization of these molecules in marine organisms are known and, more in general, there are no molecular data on terpene assembly, except for a few biosynthetic studies on algae and marine invertebrates, and for some recent information deriving from the genome sequencing of two marine bacteria.

Polyketides

Polyketides are a large and structurally diverse class of natural products that includes many different compounds with valuable biological properties. These compounds are produced by many different organisms, from protists and bacteria to plants and fungi. Knowledge of polyketide biogenesis in marine systems is still limited and the metabolic pathways operating in marine organisms are inevitably discussed in relation to terrestrial processes, especially those occurring in bacteria and plants. Although the first experiment targeting marine polyketides dates back to 1979, the number of biosynthetic studies is insignificant in comparison to the large number of cyclic and linear structures isolated. In a few cases, these structures are restricted or highly specific of marine organisms. This is the case of polypropionates synthesized by some molluscs of the order Sacoglossa which show the uncommon ability to replace one or more acetate units by propionates. Alkylpyridines and other aromatic alkanoates, produced by a few sponges and molluscs, are another outstanding example of truly marine molecules of the polyketide family. In these compounds an aromatic starter, e.g. benzoic acid or pyridine, is apparently elongated by acetate units according to the progressive scheme of polyletide assembly.

Aminoacids, peptides and nitrogen-containing compounds

New classes of nitrogen including compounds from marine organisms have been shown to possess powerful biotechnological potential, especially as drug candidates. Synthetic analogues of the C-nucleosides Spongouridine and Spongothymidine isolated from a Caribbean sponge have led later to the development of Cytosine Arabinoside, an anticancer compound. The Ecteinascidin-743 (ET743) originating from the Caribbean tunicate Ecteinascidia turbinate is the prototype of a family of isoquinoline alkaloids, e.g. jorumycin (from molluscs) and renieramycins (from sponges), emerging as novel antitumour drugs. ET743 has potent cytotoxic and antitumour activity and a potential new mechanism of action. A number of cyclic peptides, depsipeptides and linear peptides bearing uncommon amino acids have been reported from sponges, tunicates, molluscs and seaweeds. Many of these molecules show unique unprecedented structures in comparison with similar compounds from other sources; they are often cyclic or linear peptides containing unusual amino acids which are either rare in terrestrial and microbial systems or even totally novel, and also frequently containing uncommon condensation between amino acids. Cyclic and linear peptides discovered from marine animals have increased our knowledge about new potent cytotoxic, antimicrobial, ion-channel specific blockers, and many other properties with novel chemical structures associated to original mechanisms of pharmacological activity. Didemnins are a family of depsipeptides with antitumor, antiviral and immunosupressive activities primarily isolated from the Caribbean tunicate Trididemnum solidum, but later obtained from other species of the same genus.

Cytotoxic cyclic peptides have also been found in molluscs. Dolastatins are a group of cyclic and linear peptides isolated from the marine mollusc Dolabella auricularia, with prominent cell growth suppressing activity. The conotoxins isolated from molluscs of the genus Conus take part in defence, prey capture and some other biotic interactions. The majority of these peptides consist of about 8–35 amino acids in length with specific actions on ion channels and membrane receptors of excitable cells. In addition, Conus venoms also contain a heterogeneous group of peptides that are disulfide poor (e.g. the conantokins), large polypeptides (>10 kDa) or small molecules such as the biologically active amines. Since venoms are used as a survival strategy by several different species it is not surprising that the components of these venoms might exert very specific and potent effects. For this same reason animal venoms are for scientists a source of interesting bioactive molecules commonly known as toxins.

Shikimate derivatives

The anabolic shikimic acid pathway has seven steps for the biosynthesis of many aromatic compounds in a broad range of organisms, including bacteria, fungi, plants and some protozoans. Shikimate-derived metabolites are not very common in marine organisms even if a few examples of compounds derived by mixed biosynthesis have been reported in the literature. Among these the clathrins from the sponge Clathria sp., represent a plausible biosynthetic intermediate that provides an inferred link between marine sesquiterpene/benzenoids and mixed terpene/shikimate biosynthesis. Shikimate origin has been also suggested for the phenyl moiety of marine cyanobacterium metabolite barbamide.

Animals are considered to lack this pathway as inferred by their dietary requirement for shikimate-derived aromatic amino acids such as anthranilate and folate. Recently, molecular evidence has established the horizontal transfer of ancestral genes of the shikimic acid pathway into the Nematostella genome from both bacterial and eukaryotic (dinoflagellate) donors. These results provide a complementary biogenesis of shikimate-related metabolites in marine Cnidaria as a “shared metabolic adaptation” between an invertebrate host and its microbial consorts.

Physical and chemical properies of functional metabolites

The physical and chemical properties of habitats can determine the nature and success of ecological interactions. In terrestrial environments, for example, compounds with high vapor pressures (low molecular weights, hydrophobic) facilitate chemical transport in air. Because the requirement for gaseous volatility imposes strong constraints on molecular designs, the isolation and identification of signal molecules by gas chromatography and mass spectrometry is often straightforward. By comparison, much less is understood about chemically mediated interactions in aquatic habitats. Aqueous solubility (imparted mainly by electronic charge or hydrophilicity), rather than gaseous volatility, may constrain the types of substances principally acting as waterborne chemical agents. Even insoluble compounds can provide effective chemical signals when suspended and transported by fluid flow in the water column. The identities of cues mediating habitat selection (including settlement by and metamorphosis of larvae), predator avoidance, mating, and social interactions in aquatic environments have thus far proven elusive except in a few isolated cases. Yet there are numerous outstanding examples of secondary metabolites serving multiple roles and regulating the behavioral or physiological responses of individuals at lower trophic levels. Transferred to consumers at higher trophic levels, these effects have profound consequences for the distribution and abundance of organisms.

Identification of marine functional metabolites

Since the early 1980s, collaboration between chemists and ecologists has led to an increasing number of studies in which modern techniques of chemical isolation and identification are coupled with ecologically relevant laboratory and field experiments. Significant progress in identifying ecologically relevant molecules is being made for marine systems, particularly on secondary metabolites acting as chemical defenses. Most of these substances can be extracted from animals, plants, and microbes by organic solvents (such as methanol or dichloromethane). The compounds are separated by reverse phase or hydrophobic-interaction HPLC and gas chromatography before structures are identified by means of mass spectrometry, NMR, and other spectroscopic methods. Because secondary metabolites are available in partially or fully purified forms, they provide outstanding tools for quantitative studies. Such methods are currently being used to investigate the synthesis, inducibility, and seasonal and geographical variability in chemical defenses. Also under study are mechanisms of detoxification and patterns of associations (mutualism, commensalism, and parasitism), including co-evolution between chemically defended and non-defended species. These results will undoubtedly expand on the current understanding of the direct consequences of chemically mediated interactions to provide more predictive insights about population regulation and community structure. Purifications of ecologically relevant molecules other than secondary metabolites (i.e. functional metabolites) are often more challenging, and thus advances are occurring more slowly.

See also

References


The main authors of this article are Fontana, Angelo and Ianora, Adriana
Please note that others may also have edited the contents of this article.