Chapter 12 - Oleuropeic and Menthiafolic Acid Glucose Esters from Plants: Shared Structural Relationships and Biological Activities

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Abstract

Glycosylation of small lipophilic molecules is a ubiquitous process in plants that produces many important compounds. Many of these are secondary metabolites with key roles in plant abiotic and biotic stress tolerance through such processes as free radical scavenging and antimicrobial and antiherbivore defense. Most of these plant products occur as O-glycosides, with a much smaller number occurring as glucose esters of aromatic acids, and even fewer occurring as glucose esters of aliphatic acids. For example, there is a large diversity and distribution of monoterpene glycosides in plants, but relatively few monoterpene acid glucose esters have been elucidated to date. There have, however, been increasing reports of the latter esters in recent years, particularly those based on the isomers menthiafolic acid and oleuropeic acid. Although menthiafolic acid is acyclic and oleuropeic acid cyclic, the acids share similarities such as the presence of an α,β-unsaturated carbonyl group. Moreover, both monoterpene acids can occur as monoesters or diesters of glucose, or more commonly as monoesters of glucose with shared O-linked phenolic moieties such as gallic acid, noreugenin, chromenone, quercetin, or kaempferol. The combination of the α,β-unsaturated carbonyl group in both the monoterpene acid and phenolic moieties, together with the phenolic hydroxyls, gives the compounds particular biological activities with potential commercial applications. In particular, the presence of these functional groups produces a number of important therapeutic properties such as tumor inhibition, carcinogenesis suppression, and antioxidant and antiinflammatory activities. In this chapter, we review all of the glucose esters containing these monoterpenoids identified to date and describe their biological activities and commercial potential as therapeutics. We also discuss how such properties may relate to functional roles in plants such as biotic and abiotic stress responses. Finally, we collate the limited information available on their biosynthesis.

Introduction

Many functionally important plant metabolites occur as glycosides of small lipophilic molecules. The most common of these are O-glycosides, which generally form when a glucosyltransferase (GT) joins the hydroxyl group of an aglycone to the anomeric center of glucopyranose in glucosides or di-, tri-, and higher carbohydrate moieties in glycosides [1]. The transfer of a sugar onto a lipophilic acceptor via the action of glycosyltransferases changes chemical properties of the aglycone such as solubility and stability, which in turn alters bioactivity and enables access to membrane transporter systems [2]. As a consequence, the resultant glycosides have diverse activities and functions in plants and play key roles in abiotic and biotic response processes including free radical scavenging in oxidative stress tolerance and antimicrobial and antiherbivore defense.

Glucose esters of small lipophilic molecules are also widely distributed in plants and are characterized by esterification of aromatic or aliphatic acid aglycones to a carbohydrate such as glucopyranose, typically at the anomeric or primary hydroxyl positions [3]. Similar to glycosides, glucose esters also fulfill many biologically important functions in plants. Indeed, it has been suggested that neutralizing the acid group via esterification may be more advantageous than glycosylation for plants as it improves water solubility for transport, particularly in phloem sap [4]. Common examples of aromatic acid aglycones of glucose esters are the hydroxycinnamic acids caffeic, cinnamic and ferulic acids, and the trihydroxybenzoic acid gallic acid. Aliphatic acid aglycones of glucose esters can be fatty acids, iridoids, carotenoids, or terpene acids such as triterpenes (e.g., oleanolic acid), diterpenes (e.g., retinoic acid), sesquiterpenes (e.g., artemisinic acid), or monoterpenes (e.g., perillic acid; [5]). This chapter focuses on the glucose esters of particular aliphatic monoterpene acids that have received increased attention in recent times.

Only a relatively small number of monoterpene acid glucose esters have been isolated from any sources to date. This is in contrast to monoterpene glycosides which are relatively common metabolites in plants with diverse functional roles and numerous human uses based on their flavor and fragrance properties (see reviews by Vasserot et al. [6], [7], [8], [9]). Despite the apparent rarity of monoterpene acid glucose esters in general, a variety of glucose esters based on two isomeric monoterpene acids, oleuropeic acid (S)-4-(1-hydroxy-1-methylethyl)-1-cyclohexene-1-carboxylic acid (1) and menthiafolic acid (linalool-1-oic acid; 6-hydroxy-2,6-dimethyl-2,7-octadienoic acid; 5), have been found with increasing prevalence in plants in recent years and have been shown to exhibit numerous biological properties [10]. The two aliphatic acids share a number of structural similarities: they both have α,β-unsaturated carbonyls, a nonoxidizable tertiary hydroxyl at C-8, and a molecular formula of C10H16O3. They differ, however, in oleuropeic acid being cyclic and menthiafolic acid acyclic. Interestingly, both acids have also been found esterified to glucose in the same compound—froggattiside A (8; [11]). This chapter focuses on the glucose esters that contain oleuropeic and menthiafolic acids identified to date. We examine their biological activities and possible functional roles in plants and discuss how their chemical properties give them the potential for commercial application as pharmaceuticals.

Section snippets

Oleuropeyl and Menthiafoloyl Glucose Esters

Oleuropeic and menthiafolic acids have been found in their free form in plants, but their glucose esters appear to be more widely distributed (see Table 1). The apparent prevalence of glucose esters of these acids may reflect their potential functional roles (described in Functional Roles in Plants section), or it may in part be artifactual due to an experimental bias toward elucidating the structures of the glucose esters. Free oleuropeic acid has been found in olive oil extracted from the

Biological Activities

The biological activities of free oleuropeic and menthiafolic acids have not been tested extensively, but in those studies that have assessed their properties, no significant activity has been observed. For example, the inhibitory activity of oleuropeic acid isolated from Abies chensiensis was tested against lipopolysaccharide-induced nitric oxide production in a murine marcrophage cell line but was found to have no detectable activity when compared to the positive control aminoguanidine [52].

Functional Roles in Plants

There has been little research specifically addressing the biological or ecological roles of the monoterpene acid glucose esters presented in Fig. 2. The most detailed work comes from the aforementioned study that found four menthiafolic acid glucose esters in P. oleraceae [38]. That study also examined if the compounds could be induced when leaves were sprayed with a 2% aqueous solution of CuCl2. After 48 h, leaves were harvested and in those from unsprayed control plants only the monoester 4

Biosynthesis

Despite great advances in understanding plant mono- and sesquiterpene biosynthesis in the last few decades (see [89]), surprisingly little is known about the biosynthesis of monoterpene acids or the process by which they are esterified to glucose. Based largely on structural similarities, it has been suggested that oleuropeic acid is likely derived from the cyclic monoterpene α-terpineol [25], whereas menthiafolic acid is likely derived from the acyclic monoterpene linalool [90]. Studies on

Concluding Remarks

There have been increasing reports of oleuropeic and menthiafolic acid glucose esters in recent years, particularly from plants in the genus Eucalyptus. Indeed, over two thirds of known glucose esters of oleuropeic and menthiafolic acids have been described from, or detected in, the genus. Many of the compounds contain phenolic aglycones and all contain one, and often two, α,β-unsaturated carbonyls—chemical constituents that afford a number of important potential therapeutic and biological

Acknowledgement

J. Q. D. G. and I. E. W. were supported by a grant from the Australian Research Council (Project DP1094530).

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