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Monoterpene biosynthesis in marine algae

Posted on: Sunday, 5 October 2003, 06:00 CDT

Marine algae produce a variety of secondary metabolites, including monoterpenes, which present several highly unusual characteristics. The algal monoterpenes are nearly always halogenated and they possess ring structures quite unlike those in monoterpenes originating from terrestrial plants, suggesting novel biosynthetic pathways and mechanisms. Although limited in scope and number, field studies suggest that these compounds play a role in the defence of marine algae, similar to the role played by the more extensively studied terrestrial monoterpenes. This review examines the biogenetic pathways proposed for marine algal halogenated monoterpenes and compares them with the more thoroughly defined biosynthetic mechanisms of monoterpenes in terrestrial plants. A detailed characterization of monoterpene biosynthesis in cultured Ochtodes secundiramea (Rhodophyta) is also presented as a model for studying the biosynthesis of these unusual metabolites and evaluating their ecological functions.

INTRODUCTION

Monoterpenes are most commonly recognized as the flavour and aroma components found in the essential oils of many herbs and spices, as well as citrus and conifers. In terrestrial plants, monoterpenes function largely as insect pest deterrents (Pickett 1991; Pare & Tumlinson 1999), pollination attractors (Langenheim 1994) and allelopathic agents (Romagni et al. 2000). Owing to the commercial value of monoterpenes and a traditional interest in their structural chemistry, the biosynthesis of terrestrial monoterpenes has received considerable attention (Wise & Croteau 1999).

Marine algae, particularly the Rhodophyta, also produce a variety of biologically active monoterpenes, most of which are halogenated, and the cyclic monoterpenes possess carbon structures quite unlike those observed in their terrestrial counterparts (Naylor et al. 1983). The few available studies on the biological function of these marine natural products point to ecological roles such as herbivore deterrence (Paul et al. 1980, 1987). Evidence for antialgal (Konig et al. 1999b) and anti-fouling activity (Konig et al. 1999a) has also been obtained. Moreover, halomon (6R-bromo-3S-(bromomethyl)-7- methyl-2,3,7-trichloro-1-octene), an acyclic polyhalogenated monoterpene isolated from Portieria hornemannii (Lyngbye) P.C. Silva, has been shown to possess potent antitumour activity in cancer cell line assays (Fuller et al. 1992). There is also interest in using the chemical structures found in halogenated monoterpenes as a basis for insecticide development (San-Martin et al. 1991; Argandona et al. 2002).

The unusual chemical characteristics of these algal monoterpenes imply novel biosynthetic pathways and mechanisms. This paper will review the biogenetic schemes that have been proposed to rationalize these in the context of the more comprehensive knowledge we have of the mechanisms employed by terrestrial plants. A model system to explore the factors regulating the biosynthesis of halogenated monoterpenes and to define their ecological function using a microplantlet culture system of the red alga Ochtodes secundiramea (Montagne) Howe will also be described.

TERPENE BIOSYNTHESIS

Terpenoids (also referred to as isoprenoids) are polymers of five- carbon isoprene subunits and, with over 23,000 known compounds, comprise the largest single class of natural products (Connolly & Hill 1992). Although terpenes composed of hundreds of isoprene units (e.g. natural rubber) exist, the vast majority are C^sub 10^ monoterpenes, C^sub 15^ sesquiterpenes and C^sub 20^ diterpenes, containing two, three or four isoprene subunits, respectively. The enormous structural diversity of these compounds results from enzyme- catalysed cyclization of the diphosphate ester precursors [geranyl diphosphate (GDP), farnesyl diphosphate and geranylgeranyl diphosphate] into myriad cyclic and polycyclic carbon skeletons, which can be further modified by oxidation, reduction, isomerization or conjugation reactions. The limited flexibility of the C^sub 10^ precursor, GDP, restricts monoterpenes to mono- and bicyclic carbon skeletons. Indeed, GDP itself is topologically restrained from cyclization and it was only after the insightful analysis by Croteau of monoterpene synthases from sage (Salvia officinalis Linnaeus) that this substrate was recognized as the direct precursor for monoterpenes (Croteau & Karp 1979; Croteau et al. 1980). Subsequent analyses of monoterpene synthases from a multitude of plants (Croteau 1987; Wise & Croteau 1999), including liverworts (Adam et al. 1996; Adam & Croteau 1998) and a marine alga (Wise et al. 2002), have confirmed that GDP is the universal precursor for monoterpene biosynthesis.

A paradigm for monoterpene biosynthesis has evolved to rationalize the cyclization of GDP into the multitude of cyclic and bicyclic carbon skeletons observed in terrestrial plants (Croteau 1987; Wise & Croteau 1999). A key feature of this mechanism is the role of the enzyme in initiating a divalent cation-assisted ionization of the diphosphate group, with subsequent isomerization to form an enzyme-bound linalyl diphosphate (LDP) intermediate. This allows rotation about the newly formed C2-C3 single bond, positioning C1 in proximity to the C6-C7 double bond and promoting, upon ionization of the LDP intermediate, electrophilic attack on the double bond forming the cyclic [alpha]-terpinyl cation intermediate. Final quenching of this highly reactive carbocation intermediate can occur through several mechanisms generating a variety of monoterpene carbon skeletons (see Fig. 1).

Fig. 1. Monoterpene cyclization paradigm. Enzyme-bound GDP is folded into either a right- or a left-handed helical conformation. Illustrated is the pathway from a left-handed helix, which upon ionisation and isomerization yields enzyme-bound (3R)-LDP intermediate. Rotation about the newly formed C2-C3 bond, after ionization of the LDP intermediate, allows cyclization to the (4R)- terpinyl cation intermediate. Subsequent termination of the carbocation species, through a variety of pathways, provides manifold cyclic and bicyclic carbon structures. A similar pathway proceeding from the right-handed helical conformer of GDP results in the stereochemical antipodes of the structures shown above.

One of the remarkable characteristics of monoterpene synthases is the facility of these biocatalysts to produce multiple products from a single substrate. However, ascribing multiple product formation to a single enzyme can be difficult. Because the monoterpene synthases share substantial amino acid homology (Bohlmann et al. 1998), they also exhibit similar physicochemical properties and so are exceedingly difficult to isolate as individual enzymes. Thus, in plant tissues producing multiple monoterpenes, it is difficult to discern whether these result from multiple enzymes or are simply multiple products from a single enzyme. Only recently, through heterologous expression of monoterpene synthases (Colby et al. 1993), has unequivocal evidence been provided concerning this unusual catalytic capability. For example, a complementary deoxyribonucleic acid (cDNA) encoding bornyl diphosphate synthase from culinary sage (S. officinalis), functionally expressed in Excherichia coli (Migula) Costellani & Chalmers, produces (in addition to bornyl diphosphate) significant quantities of [alpha]- pinene, camphene, myrcene, limonene and terpinolene (approximately 25% of the total product) (Wise et al. 1998). Insight into the mechanistic basis for multiple product formation has recently been achieved through structural analysis of the sage bornyl diphosphate synthase (Whittington et al. 2002). Monoterpene synthases can also employ LDP or neryl diphosphate (NDP, the cis isomer of GDP) as substrate, although the product profile is usually altered from that observed with the natural substrate, GDP (Croteau 1987; Wise et al. 1998; Wise & Croteau 1999).

Fig. 2. Biogenetic schemes leading to the novel ring structures observed in eyclic halogenated monoterpenes in the marine red algae. Bromonium ion-initiated cyclizalion of myrcene yields the ochtodane ring system, whereas cyclization of ocimene yields cither the 1,3- dimethyl-3-vinyl-cyclohexane skeleton or, by ethyl migration, the 1,3-dimethyl-4-vinylcyclohexane congener.

Fig. 3. Examples of halogenated monoterpenes from marine red algae. Included are an acyclic monoterpene and examples of three typical cyclic structures. The organism producing them is listed below the compound common name.

A 1983 review listed more than 100 unique monoterpenes isolated from marine organisms (predominantly red algae) (Naylor et al. 1983). That number has approximately doubled in the past 20 years (Faulkner 1984, 1986, 1990, 1991, 1992, 1993, 1996, 1998, 2000, 2001, 2002). The vast majority of marine monoterpenes contain bromine or chlorine atoms or both, with the acyclic monoterpenes likely resulting from haloperoxidase action on either myrcene or ocimene (Hewson & Hager 1980; Butler & Walker 1993). The cyclic halogenated monoterpenes display ring structures that clearly are not elaborated from an [alpha]-terpinyl intermediate (Fig. 2) and therefore do not fit the mechanistic paradigm illustrated in Fig. 1. Fenical (1975) proposed bromonium ion-initiated cyclization to explain the bromochamigrene sesquiterpenes found in LaurenciaJ.V. Lamouroux and later extrapolated this rationale to implicate myrcene as the immediate precursor to the formation of the ochtodane ring (1- ethylidene-3,3-dimethylcyclohexane) found in marine monoterpenes (Fenical 1982). Thus, ring closure is initiated by bromonium attack on the C6-C7 olefin followed by internal addition to the resulting cationic centre by one of the remaining double bonds (Fig. 2). Similar reasoning invokes ocimene as the immediate precursor to the 1,3-dimethyl-1-vinylcyclohexane and the 2,4-dimethyl-1- vinylcyclohexane-structured types (Naylor et al. 1983). Interestingly, of the three cyclic structures found in algae (Fig. 3), only the ochtodane ring is found elsewhere; it is produced as a boll weevil (Anthonomus grandis Boheman) sex pheromone (Tumlinson et al. 1971). This ochtodane ring lacks a halogen substituent and its biosynthesis likely proceeds from protonation rather than bromonium- initiated cyclization of myrcene.

The biogenetic schemes presented above are based on relevant chemical models (Kato et al. 1976; Yoshihara & Hirose 1978; Masaki et al. 1982) and successfully predict the halogenation patterns and ring structures observed in algae. Implicit in these schemes is the role of myrcene or ocimene as the immediate precursors to the cyclic forms. Despite attempts (Barrow & Temple 1985), none of these pathways have yet been demonstrated experimentally.

Molecular biology of monoterpene synthases

Using a reverse genetic approach, the first monoterpene synthase, limonene synthase, was cloned from spearmint (Mentha spicata Linnaeus) by Colby et al. (1993). As additional terpene synthases have been revealed, certain highly conserved sequences have become apparent. For example, an (I/L/V)DDXXD motif (X = any amino acid), which provides the binding site for the divalent cation-complexed diphosphate moiety (Song & Poulter 1994; Tarshis et al. 1994; Lesburg et al. 1997; Starks et al. 1997; Whittington et al. 2002), is found in nearly all terpene synthases and prenyltransferases. This and other highly conserved motifs (Bohlmann et al. 1997; Wise et al. 1998) have provided a framework within which homology-based approaches to monoterpene synthase isolation can be developed. Thus, over a dozen monoterpene synthases, originating from both angiosperms (Colby et al. 1993; Yuba et al. 1996; Wise et al. 1998) and gymnosperms (Bohlmann et al. 1997, 1999, 2000), have now been sequenced. As yet, however, there is no molecular characterization of any monoterpene synthase from a marine alga.

Monoterpene biosynthesis in cultured Ochtodes secundiramea

Because many of the pharmacologically promising marine algal natural products cannot be synthesized economically, and because harvest from nature of the organisms that produce them is not environmentally acceptable, biotechnological methods may be required for the large-scale production of these compounds. Recently, a culture system has been developed using O. secundiramea, which produces a variety of cyclic and acyclic monoterpenes (Maliakal et al. 2001; Rorrer et al. 2001) and this provides a model for exploring the possibility of industrial production. Bioreactors facilitate manipulation of environmental conditions, such as nutrient load and balance, photoperiod and intensity, pH and temperature. Experiments with the O. secundiramea system have shown that halogenated monoterpene biosynthesis is favoured, under light saturation, by low nitrate availability (Maliakal et al. 2001), which is consistent with the carbon-nutrient balance hypothesis [that postulates that, under conditions of limited nutrients and adequate light for photosynthesis, plants will increase production of carbon-based secondary metabolites at the expense of growth rates (Bryant et al. 1984)]. In contrast, field studies to investigate intraspecific variation of ochtodene concentrations in Portieria hornemannii at different locations on Guam previously showed that neither environmental nitrogen nor phosphorus levels account for these differences (Puglisi & Paul 1997). It was suggested instead that herbivory or developmental variation, among other factors, might account for site-to-site variation in monoterpene composition. Although these two studies are not directly comparable (owing to differences in species, environment, etc.), they point out the complex relationship between environment and natural product biosynthesis, and the value of a closed culture system for examination of these phenomena.

Fig. 4. Gas chromatogram of the steam-distillation hexane extract from cultured O. secundiramea (from Wise et al. 2002). Product identification is based on mass spectral analysis. Peak 1 was identified as myrcene, peak 2 as (Z)-10-bromomyrcene, peak 3 as (E)- 10-bromomyrcene, peak 4 as a dibrominated myrcene of uncertain regiochemistry and peak 5 as a brominated monoterpene alcohol (C^sub 10^H^sub 15^BrO) of unknown structure.

Cultured O. secundiramea tissue subjected to simultaneous steam distillation-solvent extraction and analysed by gas chromatography- mass spectroscopy showed five major monoterpene components (Fig. 4). These were identified, in order of abundance (based on total ion count), as (E)-10-bromomyrcene (33.2%), myrcene (32.6%), a dibrominated myrcene (14.4%), a brominated monoterpene alcohol (5.0%) and (Z)-10-bromomyrcene (2.8%) (Wise et al. 2002). Previous analyses of dichloromethane extracts from these cultured cells provided similar results, with the addition of minor amounts of cyclic halogenated monoterpenes tentatively identified as chondrocole C (6,8-dibrom-1,4-oxido-2-ochtodene) and ochtodene (1,6- dibromo-4,8-dichloro-3-ochtodene) (Maliakal et al. 2001). In contrast, in field-collected Ochtodes sp., the halogenated monoterpenes were > 99% cyclic and myrcene was not detected (McConnell & Fenical 1978; Paul et al. 1980).

Cell-free buffer extracts of cultured O. secundiramea tissue have also provided a source of myrcene synthase. This is the first monoterpene synthase to be isolated from a marine organism. The enzyme is operationally soluble, has a molecular weight of about 69 kDa, and a pH optimum of 7.2 (Wise et al. 2002). Mechanistically, myrcene is the simplest of monoterpenes to produce, requiring only the divalent cation-assisted ionization of GDP and subsequent deprotonation at C10. To further explore the mechanism of this marine algal monoterpene synthase, the alternate substrates LDP and NDP were employed as substrates. Interestingly, NDP was converted almost exclusively to limonene, whereas reaction with LDP resulted in a suite of cyclic and acyclic monoterpenes (myrcene, cis- and trans-ocimene, limonene and terpinolene: Fig. 5). These results provide an intriguing insight into the mechanism of this enzyme. Thus, it appears that the enzyme does not catalyse the isomerization of GDP to LDP, a step necessary for cyclization of this substrate; however, when presented with a topologically suitable substrate, such as NDP, the enzyme facilitates cyclization, yielding limonene. In the case of LDP, which can assume either a cisoid or a transoid conformation, a variety of acyclic and cyclic products are produced. The limited catalytic capability of this enzyme, i.e. its inability to isomerize GDP to LDP, possibly reflects its evolutionarily ancient origin. The fact that myrcene is a major monoterpene found in cultured O. secundiramea plantlets and yet is not detected in field-collected algae, together with the observation that the cultured alga does not produce the normal complement of cyclic halogenated monoterpenes, suggests a repression of the downstream processing of myrcene. These facts also suggest that, in nature, myrcene biosynthesis is a rate-limiting step in the pathway.

Fig. 5. Reaction catalysed by the O. secundiramea myrcene synthase (from Wise et al. 2002). Cyclization occurs when the enzyme is presented with a prenyl diphosphate topologically disposed to ring formation, such as NDP. With LDP as substrate, a suite of monoterpenes is produced. Reaction with GDP yields only myrcene.

There is, as yet, no experimental evidence that cyclization of myrcene to ochtodene and related structures is enzymatically catalysed; these rearrangements can occur in the presence of bromonium ion without enzyme catalysis (Yoshihara & Hirose 1978; Masaki et al. 1982). Many species of algae, including O. secundiramea (Maliakal et al. 2001), produce haloperoxidases capable of oxidizing bromine and chlorine (Hewson & Hager 1980; Butler & Walker 1993). For many years, it was generally thought that the vanadium haloperoxidases from marine algae produced freely soluble HOBr (or Br^sub 2^ or Br^sub 3^^sup -^); thus, halogenation of organic compounds would be expected to show low enantio- and regioselectivity (Frassen 1994). Nonenzymatic bromonium-initiated cyclization, however, is inconsistent with the stereospecificity observed in the algal metabolites. There is new evidence that certain marine haloperoxidases do demonstrate selectivity in binding organic substrates (Butler 1998) and that they also catalyse regiospecific oxidations (Martinez et al. 2001). Thus, it appears likely that an enzyme with haloperoxidase activity is involved in the cyclization of halogenated monoterpenes in marine algae.

INDUCIBLE DEFENCES IN MARINE ALGAE

Biosynthesis of secondary metabolites as a defence against herbivores or pathogens incurs a high metabolic cost (Gershenzon 1994; Baldwin 2001). One way to reduce unnecessary metabolic expenditure is through inducible pathways, such as phytoalexin biosynthesis in terrestrial plants. Up-regulation of terpenoid biosynthesis in response to wounding has been well established to occur in land plants (Lewinsohn et al. 1991; Pickett 1991; Pare & Tumlinson 1999). Whether or not marine algae employ inducible chemical defences has received relatively little attention (Hay 1996), although some studies suggest that they do (Van Als\tyne 1988; Cronin & Hay 1996; Ender et al. 1999; Toth & Pavia 2000). Oligosaccharides are well-characterized elicitors of inducible defences in terrestrial plants (Ryan & Farmer 1991). Originally identified as [beta]-glucan oligomers from pathogenic fungi (Ayers et al. 1976a, b), oligosaccharides originating from both invading pathogens and the plant itself are now recognized as signalling molecules that promote numerous physiological responses, including the generation of reactive oxygen species (H^sub 2^O^sub 2^, O^sub 2^^sup -^) (Ryan 1987; Ryan & Farmer 1991).

Marine algae are now known to possess similar eliciting mechanisms (Potin et al. 1999). Thus, the red alga Gracilaria conferta (Schousboe ex Montagne) Feldmann & G. Feldmann responded to treatment with agar, agarose and certain agarose degradation products with an immediate oxidative burst (within 3 min), generating relatively high levels of H^sub 2^O^sub 2^. This oxidative burst was accompanied by an increase in bromoperoxidase activity (Weinberger et al. 1999). Whether the bromoperoxidase activity simply reflects an increase in substrate availability (H^sub 2^O^sub 2^) and a means of detoxification, or whether it also provides additional antimicrobial metabolites, is not clear. The elicited response, in general, has been shown to be an effective defence against epiphytic bacteria (Weinberger & Friedlander 2000). Similar responses, evoked by oligoguluronates, have been reported in the brown alga Laminaria digitata (Hudson) J.V. Lamouroux (Kupper et al. 2001). Because oligosaccharide elicitation can be quite sensitive to chemical composition, branching and polymer length, definitive demonstration of this phenomenon can be technically challenging. It has not been evaluated in any algae producing halogenated monoterpenes. A relationship between elicited oxidative bursts, increased haloperoxidase activity and the biosynthesis of halogenated monoterpene does seem plausible, however.

FUTURE PROSPECTS

The culture system for O. secundiramea represents an unparalleled opportunity to investigate the biosynthesis and chemical ecology of halogenated monoterpenes. This model system can be manipulated to evaluate a broad range of environmental and biological factors affecting the metabolism of these secondary products. Assuming that GDP is the universal precursor to all monoterpenes, then a myrcene synthase is requisite for the biogenetic scheme proposed by Fenical (1982). Identification of this enzyme in bioreactor cultures allows evaluation of culture conditions that affect its expression and correlation of myrcene synthase expression with the production of more complex monoterpenes. Isolation of the myrcene synthase encoding cDNA, either through a reverse genetic approach or a homology-based screening strategy, using extant monoterpene synthase sequence data, is feasible. With these tools in hand, it will be possible to study the regulation of monoterpene biosynthesis at the molecular level. Northern and Western blot analyses, for example, could be employed to determine the level at which monoterpene biosynthesis is controlled. Moreover, this system provides an excellent vehicle with which to test the effects of mechanical wounding, oligosaccharide signalling and other known or as yet unknown elicitors of secondary metabolism. If conditions promoting biosynthesis of the cyclic compounds can be determined, then molecular methods such as subtractive hybridization and differential display polymerase chain reaction (PCR) can be employed with reverse- transcriptase-PCR products or cDNA libraries from the elicited vs the nonelicited plants to identify the gene products involved. Alternatively, the same molecular approaches may be used to identify differences in gene expression between the cultured alga and the native organism, again leading to the isolation of the relevant cDNA and ultimately the enzyme or enzymes responsible for halogenated monoterpene biosynthesis.

Phycologia (2003) Volume 42 (4), 370-377

Published 4 September 2003

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Accepted 23 January 2003

MITCHELL L. WISE*

Cereal Crops Research Unit, Agricultural Research Service, United States Department of Agriculture, Madison, WI 53726, USA

M.L. WISE. 2003. Monoterpene biosynthesis in marine algae. Phycologia 42: 370-377.

* Corresponding author (mlwise@wise.edu).

Copyright International Phycological Society Jul 2003

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