Lipoxygenases: Potential starting biocatalysts for the synthesis of signaling compounds

Biotechnology Advances 30 (2012) 1524–1532

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Research review paper

Lipoxygenases: Potential starting biocatalysts for the synthesis of signaling compounds Young-Chul Joo, Deok-Kun Oh ⁎ Department of Bioscience and Biotechnology, Konkuk University, 1 Hwayang-Dong Gwangjin-Gu, Seoul 143-701, Republic of Korea

a r t i c l e

i n f o

Available online 17 April 2012 Keywords: Lipoxygenase Signaling compounds Hydroperoxy fatty acid Pathway classification Applications

a b s t r a c t Lipoxygenases (LOXs) have attracted a great deal of attention as potential starting biocatalysts for synthesizing signaling compounds. Significant advances during the past decade include the discovery of regiospecific LOXs and structural investigation for their diverse regiospecificity. Eight regiospecific (5-, 8-, 9-, 10-, 11-, 12-, 13-, and 15-) LOXs catalyze positional-specific dioxygenation of polyunsaturated fatty acids, forming positional-specific hydroperoxy fatty acids that are further metabolized into signaling compounds. The LOXderived signaling compounds can be applied not only for clinical uses but also for industrial uses. For example, animal lipoxin LXA4, plant jasmonic acids, plant green leaf volatiles, and bacterial lactones have been used as anti-inflammatory agents, anti-pest agents, flavors, and food additives, respectively. Prostaglandins, as controllers of hormone regulation and cell growth, are also suggested as LOX-derived compounds in corals. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . LOX-catalyzed pathways . . . . . . . . . . . . Classification of LOXs . . . . . . . . . . . . . . 3.1. Classical LOXs . . . . . . . . . . . . . . 3.2. Fusion-LOX . . . . . . . . . . . . . . . 3.3. Mini-LOX . . . . . . . . . . . . . . . . 3.4. Mn-LOX . . . . . . . . . . . . . . . . . 4. Structure and substrate specificity of LOXs . . . . 4.1. Structure . . . . . . . . . . . . . . . . 4.2. Substrate specificity . . . . . . . . . . . 5. Applications of LOX-derived signaling compounds 5.1. Metabolites from animals. . . . . . . . . 5.2. Metabolites from plants . . . . . . . . . 5.3. Metabolites from microorganisms . . . . . 6. Production of LOX-derived signaling compounds . 6.1. Production of prostaglandins . . . . . . . 6.2. Production of jasmonic acids . . . . . . . 6.3. Production of green leaf volatiles . . . . . 6.4. Production of lactones . . . . . . . . . . 7. Conclusions and perspectives . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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⁎ Corresponding author. Tel.: + 82 2 454 3118; fax: + 82 2 444 6176. E-mail address: [email protected] (D.-K. Oh). 0734-9750/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Inc. All rights reserved. doi:10.1016/j.biotechadv.2012.04.004

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1. Introduction Lipoxygenases (LOXs; EC 1.13.11) are a family of dioxygenases that catalyze regio- and stereo-specific dioxygenation of polyunsaturated fatty acids with one or several cis, cis-1,4-pentadiene units to form hydroperoxy fatty acids (Andreou and Feussner, 2009). In 1932, the first LOX, lipoxidase, was reported as an enzyme involved in lipid oxidation in soybeans (Andre and Hou, 1932). The enzyme is widely distributed in a large variety of organisms such as mammals (Gilbert et al., 2011; Johannesson et al., 2010), fishes (Jansen et al., 2011), plants (Acosta et al., 2009; Szymanowska et al., 2009), mosses (Senger et al., 2005), corals (Koljak et al., 1997; Mortimer et al., 2006), algae (Andreou et al., 2009), mushrooms (Bisakowski et al., 2000), fungi (Brodhun and Feussner, 2011), yeast (Shechter and Grossman, 1983), and bacteria (Koeduka et al., 2007; Lang et al., 2008), suggesting that LOX is an important biological enzyme. LOX produces hydroperoxy fatty acids that are further metabolized into various signaling compounds, such as leukotrienes and lipoxins in animals (Haeggstrom and Funk, 2011; Okunishi and Peters-Golden, 2011); prostaglandin-like molecules, which are suggested as LOX-derived compounds in corals (Koljak et al., 1997); green leaf volatiles (Allmann et al., 2010; von Merey et al., 2011; Yuan et al., 2009) and jasmonic acids in plants (Allmann and Baldwin, 2010; Mosblech et al., 2009); and lactones in microorganisms (Guo et al., 2011b; Huang and Schwab, 2011). The general relationship between LOX family and these signaling compounds has not been reviewed. Thus, in this review, we focus on the diverse regiospecificity of LOXs for the synthesis of various signaling compounds. 2. LOX-catalyzed pathways LOX-catalyzed pathways, from membrane lipids to signaling compounds in animals, corals, plants, bacteria, and fungi, are presented in Fig. 1. Phospholipase hydrolyzes membrane lipids to form polyunsaturated fatty acids and lipophilic substances. These polyunsaturated fatty acids, such as arachidonic acid (AA), α-linolenic acid (ALA), oleic acid (OA), and linoleic acid (LA), serve as LOX substrates. LOX

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major substrates include AA in animals and corals, ALA in plants, AA and ALA in fungi, and AA, LA, and OA in bacteria. Eight regiospecific (5-, 8-, 9-, 10-, 11-, 12-, 13-, and 15-) LOXs are known to catalyze positional-specific peroxidation of polyunsaturated fatty acids, producing positional hydroperoxy fatty acids, which are readily reduced to hydroxy fatty acids under physiological conditions. Animal 5-, 8-, 12-, and 15-LOXs and fungal and bacterial 15-LOX convert AA to 5-, 8-, 12-, and 15-hydroperoxyeicosatetraenoic acids (HPETEs), which are reduced to 5-, 8-, 12-, and 15-hydroxyeicosatetraenoic acids (HETEs), respectively. Plant 9- and 13-LOXs, and fungal 11- and 13-LOXs convert ALA to 9-, 11-, and 13-hydroperoxyoctadecatrienoic acids (HPOTs). Bacterial 10-LOX converts OA to 10-hydroperoxyoctadecenoic acid (HPOE) and bacterial 9-, 11-, and 13-LOXs convert LA to 9-, 11-, and 13hydroperoxyoctadecadienoic acids (HPODs), respectively (Koeduka et al., 2007; Lang et al., 2008; Vance et al., 2004; Vidal-Mas et al., 2005). The chemical structures of fatty acid substrates and hydroperoxy fatty acid products of LOX superfamily are presented in Fig. 2. These hydroperoxy fatty acids are metabolized into various signaling compounds, including leukotrienes, lipoxins, green leaf volatiles, jasmonic acids, and lactones, via reactions mediated by several enzymes and/or β-oxidation degradation pathways. In animals, lipoxin A4 (LXA4) is formed from 5-HPETE through the combined action of 5-LOX and 12- or 15-LOX. LXA4 is also synthesized directly from 15HETE by 5-LOX (Fig. 1). Prostaglandins are produced from AA in a cyclooxygenase (COX)-catalyzed pathway (Simmons et al., 2004). Alternatively, it has been suggested that prostaglandin-like molecules are produced from 8-HPETE by several enzyme reactions in corals (Koljak et al., 1997). In plants, 13-HPOT is metabolized to jasmonic acids through the sequential reactions of allene oxide synthase, allene oxide cyclase, 12-oxopendienoic acid (OPDA) reductase, and βoxidation degradation (Andreou et al., 2009). 9- and 13-HPOTs are converted to green leaf volatiles, such as C6- and C9-aldehydes and C6- and C9-alcohols, by hydroperoxide lyase (HPL) and alcohol dehydrogenase (ADH) (Gigot et al., 2010). The hydroxy fatty acids 5-, 8-, 12-, and 15-HETEs, 8,9-epoxy eicosatetraenoic acid (EETE), 9-, 11-, and 13hydroxyoctadecatrienoic acids (HOTs), 10-hydroxyoctadecenoic acid (HOE), 9- and 13-hydroxyoctadecadienoic acid (HOD), leukotriene B4 (LTB4), and LXA4 can be metabolized to lactones through β-oxidation

Fig. 1. LOX-catalyzed pathways from membrane lipids to signaling compounds in animals, corals, plants, bacteria, and fungi. Abbreviations: PGG2, prostaglandin G2; PGH2, prostaglandin H2; OPC-8:0, 3-oxo-2-(2′-pentenyl)cyclopentane-1-octanoic acid.

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Fig. 2. Fatty acid substrates and hydroxy fatty acid products for LOX superfamily enzymes.

degradation (Ghosh and Myers, 1998; Haffner and Tressl, 1996; Kiss et al., 2000).

with a low molecular mass (Andreou et al., 2010) and LOXs from most fungi are non-heme-Mn2+-containing enzymes known as Mn-LOXs (Brodhun and Feussner, 2011).

3. Classification of LOXs 3.1. Classical LOXs On basis of the major regiospecificity required for the oxygenation of polyunsaturated fatty acids, LOX family is classified as ten types, which are 5-, 8-, 9-, 10-, 12-, 13-, 15-, fusion-, mini-, and Mn-LOXs. LOX family enzymes from typical source organisms are shown in Table 1. Animal 5-, 8-, 12-, and 15-LOXs, plant 9- and 13-LOXs, and bacterial 9-, 10-, 13-, 15-LOXs are non-heme-iron-containing enzymes. 8-LOX from the coral Plexaura homomalla (Koljak et al., 1997) and 9-LOXs from the cyanobacteria Acaryochloris marina (Gao et al., 2010) and Anabaena sp. (Schneider et al., 2007) are fusionLOXs. LOX from the cyanobacterium Cyanothece sp. is a mini-LOX

5-LOX (EC 1.13.11.34) is a non-heme-iron-containing monomeric enzyme, consisting of 672 or 673 amino acids. The enzyme is present in animals, including Bos taurus (bovid), Homo sapiens (human), Mesocricetus auratus (golden hamster), Mus musculus (mouse), Rattus norvegicus (rat), and Sus scrofa (wild pig) and the plant Solanum tuberosum (potato) (Gilbert et al., 2011; Skaterna et al., 2010; Walther et al., 2011; Zou et al., 2009). 5-LOX converts AA to 5HPETE. The sequential reactions catalyzed by 5-LOX also convert AA to LTA4, which functions as a lipid mediator of inflammation. This

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Table 1 Classification of LOX superfamily according to enzyme type and typical source organism. Enzyme type (EC no.) Non-heme-iron-LOX 5-LOX (EC 1.13.11.34)

8-LOX (EC 1.13.11.40) 9-LOX (EC 1.13.11.58)

10-LOX (EC 1.13.11.-) 12-LOX (EC 1.13.11.31)

13-LOX (EC 1.13.11.12)

15-LOX (EC 1.13.11.33)

Fusion-LOX (EC 1.13.11.-) 8-LOX 9-LOX Mini-LOX (EC 1.13.11.-) 9-LOX 11-LOX Mn-LOX (EC 1.13.11.45) 13-LOX

Typical organism

Accession no.

Reference

Homo sapiens Mus musculus Solanum tuberosum Rattus norvegicus Mus musculus Arabidopsis thaliana Glycine max Hordeum vulgare Nostoc sp. Oryza sativa Solanum tuberosum Pseudomonas aeruginosa Homo sapiens Mus musculus Rattus norvegicus Arabidopsis thaliana Glycine max Hordeum vulgare Nostoc punctiforme Oryza sativa Solanum tuberosum Glycine max Homo sapiens Mus musculus Pseudomonas aeruginosa Rattus norvegicus

P09917 P48999 O49150 P12527 B1ASX6 Q06327 P08170 P29114 Q8YK97 Q76I22 P37831 Q8RNT4 P18054 P39655 Q02759 P38418 Q43446 P93184 B2J873 Q7XV13 O24370 P08170 P16050 O35936 Q9I4G8 Q8K4F2

Gilbert et al. (2011) Walther et al. (2011) Skaterna et al. (2010) Zou et al. (2009) Schweiger et al. (2007) Bannenberg et al. (2009) Zheng and Brash (2010) Garbe et al. (2006) Lang et al. (2008) Wang et al. (2008) Nam et al. (2008) Vidal-Mas et al. (2005) Guo et al. (2011a) Piao et al. (2008) Sakuma et al. (2010) Bannenberg et al. (2009) Chohany et al. (2011) Garbe et al. (2006) Koeduka et al. (2007) Wang et al. (2008) Nam et al. (2008) Caballero et al. (2010) Toledo et al. (2011) Suraneni et al. (2010) Vance et al. (2004) Cho et al. (2005)

Plexaura homomalla Anabaena sp.

O16025 Q8YK97

Neau et al. (2009) Schneider et al. (2007)

Anabaena sp. Cyanothece sp.

Q8YK97 C7QT85

Zheng et al. (2008) Andreou et al. (2010)

Gaeumannomyces graminis

Q8X151

Oliw et al. (2011)

enzyme is a target for pharmaceutical intervention in various diseases such as asthma, cancer, and cardiovascular diseases (Radmark and Samuelsson, 2009). 8-LOX (EC 1.13.11.40) is a non-heme-iron-containing enzyme, which has been reported in mice (Schweiger et al., 2007), in corals (Brash et al., 1987, 1996), in crustacean (Hampson et al., 1992), in echinoderms (Hawkins and Brash, 1987; Meijer et al., 1986), and in nervous system cells (Steel et al., 1997). The enzyme catalyzes not only the dioxygenation of AA into 8-HPETE but also the dehydration of 8-HPETE to yield 8,9-LTA4 (Kawajiri et al., 2005) (Fig. 1). 9-LOX (EC 1.13.11.58) is a non-heme-iron-containing monomeric enzyme with 741–886 amino acids. The enzyme exists in plants, including Arabidopsis thaliana (mouse-ear cress), Glycine max (soybean), Hordeum vulgare (barley), Lens culinaris (lentil), Oryza sativa subsp. japonica (rice), Phaseolus vulgaris (kidney bean), Pisum sativum (garden pea), Solanum lycopersicum (tomato), S. tuberosum, and bacteria, including Nostoc sp. (cyanobacterium) and Thermoactinomyces vulgaris (bacterium) (Bannenberg et al., 2009; Garbe et al., 2006; Iny et al., 1993; Lang et al., 2008; Nam et al., 2008; Wang et al., 2008; Zheng and Brash, 2010). 9-LOX catalyzes the conversion of ALA to 9-HPOT. Most 9-LOX products are involved in physiological functions, such as bacteria-induced hypersensitive responses, seed defense mechanism against pathogen infection, and cell wall modifications (Huang and Schwab, 2011). 10-LOX (EC 1.13.11.-) is a non-heme-iron-containing monomeric enzyme containing 685 amino acids (Vidal-Mas et al., 2005). The presence of this enzyme has been reported in only one bacterium Pseudomonas aeruginosa. 10-LOX converts OA to 10-HPOE. However, the metabolic pathway of OA and the physiological function of 10LOX products are not understood.

12-LOX (EC 1.13.11.31) is a non-heme-iron-containing monomeric enzyme, consisting of 663 amino acids. The enzyme exists in animals, including B. taurus, Danio rerio (zebrafish), H. sapiens, M. musculus, Oryctolagus cuniculus (rabbit), R. norvegicus, and S. scrofa (Guo et al., 2011a; Piao et al., 2008; Sakuma et al., 2010). 12-LOX catalyzes the dioxygenation of AA into 12-HPETE, which is transformed to the 12-epoxy fatty acids hepoxilins as pro-inflammatory agents (Fig. 1). The enzyme plays a role in several diseases, including inflammation, hypertension, and diabetes (Dobrian et al., 2011). 13-LOX (EC 1.13.11.12) is a non-heme-iron-containing monomeric enzyme with 896–941 amino acids and exists in a large variety of plants (Bannenberg et al., 2009; Chohany et al., 2011; Garbe et al., 2006; Koeduka et al., 2007; Nam et al., 2008; Wang et al., 2008). The enzyme catalyzes the conversion of ALA to 13-HPOT, which is further metabolized to green leaf volatiles and jasmonic acids. 15-LOX (EC 1.13.11.33) is a non-heme-iron-containing monomeric enzyme, consisting of 662–685 amino acids. The enzyme is widely found in animals, plants, bacteria, and fungi, including G. max, H. sapiens, Ixodes scapularis (black-legged tick), M. musculus, O. cuniculus, Pongo abelii (Sumatran orangutan), P. aeruginosa, R. norvegicus (rat), Saprolegnia parasitica (fungus), Sarcolobus globosus (twining shrub), and S. scrofa (Caballero et al., 2010; Cho et al., 2005; Suraneni et al., 2010; Toledo et al., 2011; Vance et al., 2004). 15-LOX exhibits broad substrate specificity for fatty acids and their derivatives. The enzyme effectively oxygenates all major naturally occurring fatty acids such as AA, LA, ALA, and eicosapentaenoic acid (EPA). Moreover, phospholipids, cholesterol esters, and mono-, di-, and tri-acylglycerols containing fatty acids, as well as more complex lipid–protein molecules, can serve as substrates for this enzyme. 15-LOX is involved in cell differentiation, inflammation, asthma, carcinogenesis, and

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atherogenesis (Cimen et al., 2011; Dobrian et al., 2011; Toledo et al., 2011). 3.2. Fusion-LOX Fusion-LOX (EC 1.13.11.-) is a heme-containing monomeric LOX fused with an allene oxide synthase. Fusion 8-LOXs from the corals P. homomalla, Clavularia viridis, and Gersemia fruticosa, which contain 1066 amino acids, convert AA to 8-HPETE (Neau et al., 2009), which can be further converted to allene epoxide through the allene oxide synthase activity of the fusion-LOXs. However, the biosynthesis from allene epoxide to prostaglandins in fusion 8-LOX remains has not been observed (Koljak et al., 1997). Fusion 9-LOXs from the cyanobacteria Anabaena sp., with 773 amino acids, and A. marina, with 805 amino acids, convert LA to 9-HPOD (Gao et al., 2010; Schneider et al., 2007). 3.3. Mini-LOX The molecular masses of most LOXs are 75–80 kDa in animals and 94–104 kDa in plants. However, two LOXs with low molecular masses, which are non-heme-iron-containing enzymes, exist in cyanobacteria and are referred to as mini-LOXs (EC 1.13.11.-). MiniLOX from Anabaena sp. (9-LOX), with a molecular mass of 49 kDa, consists of 430 amino acids. This enzyme catalyzes the conversion of LA to 9-HPOD as the major product (Zheng et al., 2008). The molecular mass of mini-LOX from Cyanothece sp. (11-LOX), with 569 amino acids, is 65 kDa. The mini-LOX has high activity toward LA, which is converted to 11-HPOD (Andreou et al., 2010). 3.4. Mn-LOX Mn-LOX (EC 1.13.11.-) is found in many fungi, such as Gaeumannomyces graminis var. avenae and G. graminis var. tritici, Gaeumannomyces candidum, various Mortierella strains, Penicillium camemberti, Penicillium roqueforti, Terfezia claveryi, and Thermomyces lanuginosus (Brodhun and Feussner, 2011). Mn-LOX is an Mn 2+-dependent enzyme containing 618 amino acids and catalyzes the oxidation of ALA to 11- and 13-HPOT (Oliw et al., 2011). 4. Structure and substrate specificity of LOXs 4.1. Structure The structures of 5-, fusion 8-, 9-, 10-, 12-, 13-, and 15-LOXs have been determined (Fig. 2). LOXs possess single-polypeptide-chain proteins, which consist of a smaller N-terminal β-barrel domain and a larger C-terminal subunit that harbors the catalytic non-heme iron. The N-terminal β-barrel domain is not essential for catalytic activity but is involved in membrane binding and activity regulation (Walther et al., 2011). An aromatic amino acid (tyrosine) in the N-terminal domain is tightly associated with the C-terminal subunit, which is important for protein stability and catalytic activity (Ivanov et al., 2011). On the basis of the determined structure of LOX, a representative proposed active site structure of rabbit 15-LOX docked with the substrate AA is shown in Fig. 3. The metal-binding site consists of four histidines and C-terminal isoleucine (His361, His366, His541, His545, and Ile663 in rabbit 15-LOX). Other LOXs contain three histidine and one asparagine or serine rather than four histidines. The central cavity of the enzyme, which comprises the substrate-binding pocket, is indicated in the metal-binding site and peripheral residues of AA (Phe353, Glu375, Arg403, Ala404, Ile418, and Ile 593 in rabbit 15-LOX). A dynamic oxygen access channel is present in soybean 9-LOX, rabbit 15-LOX, and P. aeruginosa 10-LOX. All channels connect the

Fig. 3. Proposed active-site structure of rabbit 15-LOX docked with the substrate AA. Active-site residues include metal-binding residues (dark red color), substratebinding residues (green color), arachidonic acid (pink color), and Fe2+ (red color).

protein surface at an active site region of high oxygen affinity. This region is localized opposite to the non-heme iron, regulating the reaction specificity of LOXs (Garreta et al., 2011). 4.2. Substrate specificity The regio- and stereo-specificity of LOXs depends on the reaction pH, depth and width of the substrate-binding pocket, head-to-tail orientation of the incoming polyunsaturated fatty acid substrate (carboxyl-end or tail-end first), specific hydrogen abstraction (L- or D-hydrogen), positions of oxygenation (−2 or + 2 direction), and oxygenation side to the substrate (same or opposite) (Bannenberg et al., 2009; Coffa and Brash, 2004; Walther et al., 2009). The proximity of the C-3 methylene group of cis,cis-1,4-pentadiene in polyunsaturated fatty acid to catalytic iron is a key determinant for positional control (Haeggstrom and Funk, 2011). The R and S stereospecificity is determined by the oxygenation positions. S-form LOX is oxygenated deeper in the substrate-binding pocket, whereas R-form LOX is oxygenated shallower in the pocket. S-form LOX contains a conserved alanine in a critical position of the active site, whereas R-form LOX contains a conserved glycine. Alanine and glycine determine the oxygenation positions (Coffa and Brash, 2004). However, mutation experiments in which alanine was changed to glycine have shown that these residues in LOXs may not always predict reaction specificity (Jansen et al., 2011). Positional specificity was shown to be altered through site-directed mutagenesis of specificity determinants. Alteration of 12-LOX (or 15-LOX) to 15-LOX (or 12-LOX) (Vogel et al., 2010), 9-LOX to 13-LOX (Andreou et al., 2008), and 5-LOX to 8-LOX and 8/15-LOX (Schwarz et al., 2001) has been reported. 5. Applications of LOX-derived signaling compounds LOX converts polyunsaturated fatty acids to hydroperoxy fatty acids, which reduce to hydroxy fatty acids. Hydroxy fatty acids have been utilized as starting materials for resins, waxes, nylons, plastics, lubricants, biopolymer, and biodiesel, and as additives in coatings and paintings because of their increased reactivity compared to non-hydroxylated fatty acids (Hou, 2009). LOX-derived signaling compounds, such as leukotrienes, lipoxins, jasmonic acids, green leaf volatiles, and lactones have important biological functions, including cell proliferation, apoptosis, inflammation, cell-to-cell communication,

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metabolism, and migration (Diggle et al., 2007; Howe and Jander, 2008; Hughes and Sperandio, 2008; Romero-Guido et al., 2011; Wymann and Schneiter, 2008; Yuan et al., 2009). These signaling compounds can be applied not only for clinical uses such as treatment of inflammation, cancer, and metabolic disease but also for industrial uses such as pest control, food storage, and flavor enhancement.

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species removal, thermo-tolerance, and environmental stress adaptation (Yuan et al., 2009). Green leaf volatiles are important contributors to fruit and vegetable flavors and can be extracted from plants or chemically synthesized. However, chemical synthesis is not favored because consumers strongly prefer natural flavors. Moreover, extraction is very expensive. Thus, biocatalytic processes for green leaf volatiles should be developed (Buchhaupt et al., 2012; Gigot et al., 2010).

5.1. Metabolites from animals 5.3. Metabolites from microorganisms In animals, the typical leukotrienes LTA4 (Fig. 4a) and LTB4 (Fig. 4b) are pro-inflammatory agents involved in inflammation, programmed cell death processes, asthma, cancer, and heart disease (Burridge, 2011; Hersberger, 2010; Wymann and Schneiter, 2008). 5-LOX and LTA4 hydrolase inhibitors, which inhibit the formation of LTA4 and LTB4, respectively, act as anti-cancer agents, thereby suppressing tumor cell growth (Schneider and Pozzi, 2011). The typical lipoxin LXA4 (Fig. 4c) is an anti-inflammatory, organ-protective, and anti-fibrotic mediator. LXA4 inhibits leukotriene-stimulated interactions of human leukocytes and is a leading structure for developing drugs to prevent inflammation (Das, 2011). The COX-derived compounds prostaglandins are also suggested as LOX-derived compounds in corals. Prostaglandins play central roles in the maintenance of pregnancy and induction of labor (Khan et al., 2008). Prostaglandins regulate inflammatory processes and calcium transport and control hormone regulation and cell growth (Scher and Pillinger, 2009). Prostaglandin analogs are currently the most important agents in the medical treatment of glaucoma and pulmonary arterial hypertension (Mubarak, 2010). 5.2. Metabolites from plants In 1962, the first isolation of jasmonic acid methyl ester had reported the essential oil of Jasminum grandiflorum (Demole et al., 1962). In plants, jasmonic acids such as (+)-7-isojasmonic acid (Fig. 4d) play important roles in programmed cell death at wound sites, sex determination, regulation of growth and development, senescence, and healing and defense processes (Howe and Jander, 2008; Mosblech et al., 2009). Jasmonic acids are used in pest control because they stimulate natural anti-pest defenses of plants without inhibiting plant growth. The green leaf volatiles C6- and C9-aldehydes and C6- and C9-alcohols include (Z)-3-nonenol (Fig. 4e) and (E)-2-hexenal (Fig. 4f). These compounds are involved in a variety of ecological functions such as plant defense against insects, pollinator attraction, plant– plant communication, plant–pathogen interactions, reactive oxygen

Bacterial lactones are quorum-sensing signaling molecules involved in cell-to-cell communication and anti-microbial functions (Hughes and Sperandio, 2008). γ-Dodecalactone activates human natural killer cells to kill tumor cells (Chen et al., 2010). Lactones, including γ-decalactone (Fig. 4g), γ-dodecalactone (Fig. 4h), γnonanolide, and δ-decanolide, have been used as food additives in the food industry because they impart fruit and dairy flavors (Huang and Schwab, 2011). Recently, microbial conversion of hydroxy fatty acids to lactones has been examined because of the increased demand for natural flavors. 6. Production of LOX-derived signaling compounds 6.1. Production of prostaglandins The pathogenic yeasts Cryptococcus neoformans and Candida albicans produce the animal prostaglandin E2 without a COX (ErbDownward and Huffnagle, 2007; Noverr et al., 2001). The pathogenic fungi have the ability to produce prostaglandin E2, prostaglandin D2 and prostaglandin F2α from AA, and the fungi-derived prostaglandins can inhibit lymphocyte proliferation that causes the development of the potential atopic disease (Noverr et al., 2002). Moreover, it has been suggested that LOX-derived prostaglandin-like molecules are produced from 8-HPETE by several enzyme reactions in corals (Koljak et al., 1997). These results suggest that prostaglandins known as COX-derived signaling compounds may be LOX-derived signaling compounds. However, the participation of LOX to synthesize prostaglandins should be proved by providing further exact evidence. 6.2. Production of jasmonic acids Jasmonic acids in plant defense response is usually induced as an invader elicitor signal or itself inducer (Zhao et al., 2005). The elicitation process of jasmonic acid synthesis requires fungal cell walls and

Fig. 4. Examples of LOX-metabolized signaling compounds in animals, plants, and microorganisms.

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fragments that lead to a rapid conversion of jasmonic acid from ALA in plants (Mueller et al., 1993). The maximum amount of jasmonic acid by elicitor-treated Rauvolfia canescens was 1370 ng per g dry cell weight (Farmer, 1994). Jasmonic acids have been detected in diverse plants such as algae, mosses, and fungi. The fungi Fusarium oxysporum and Aspergillus niger produce 20–25 types of jasmonic acids (Wasternack, 2007). The accumulated amount of (+)-7-iso-jasmonic acid in the culture medium of Botryodiplodia theobromae for 10 days is 914 mg/l (Eng et al. 1998). This is the highest production of jasmonic acid. 6.3. Production of green leaf volatiles The production of green leaf volatiles has been performed by plant extracts. However, this method has some disadvantages, including the low conversion yield from oil and the formation of undesired by-products. In contrast, green leaf volatiles can be obtained with high level by enzymatic process (Gigot et al., 2010). For an example, vegetable oils are converted by soybean LOX and recombinant alfalfa HPL to the green leaf volatiles hexanal and 2(E)- or 3(Z)-hexenal with a yield of 50% for hexanal and 26% for hexenal without no side products (Noordermeer et al., 2002). The two enzymes produce 2 g/l hexanal for 145 min with the highest concentration ever reported. Recently, the soybean LOX and watermelon HPL genes were cloned and overexpressed in the yeast Saccharomyces cerevisiae. The recombinant cells, as a cell factory, convert ALA to 2(E)-hexenal and 3(Z)hexenal (Buchhaupt et al., 2012). 6.4. Production of lactones LOXs convert unsaturated fatty acids to hydroxy fatty acids and leukotrienes, which are metabolized to δ- and γ-lactones through β-oxidation degradation and lactonization of yeast (Ghosh and Myers, 1998; Haffner and Tressl, 1996; Kiss et al., 2000). In the lactonization, hydroxy fatty acid with a hydroxyl group in even position is converted to γ-lactone, whereas that in odd position is converted to δ-lactone. Many studies have been focused on the production of γ-decalactone from ricinoleic acid among the production of lactones because the hydroxyl fatty acid, as a convenient substrate, represents almost 90% of hydrolyzed castor oil (Wache et al., 2002). The maximal production of lactone is reported in the yeast Yarrowia lipolytica, which produces 12.5 g/l γ-decalactone from castor oil after 52 h (Romero-Guido et al., 2011). 7. Conclusions and perspectives LOXs in many strains of animals, plants, and fungi have been extensively studied, whereas bacterial LOXs, except cyanobacterial LOXs, have been reported in only two strains, P. aeruginosa (VidalMas et al., 2005) and T. vulgaris (Iny et al., 1993). Thus, bacteria may be good sources for obtaining diverse-types of LOXs. Many putative bacterial LOX sequences can be obtained from GenBank; these sequences contain the conserved active-site residues of previously characterized LOXs. These genes should be cloned and expressed, and the proteins must be characterized and used for synthesizing signaling compounds. Generally, AA, ALA, and OA and LA serve as substrates for animal, plant, and bacterial LOXs, respectively. However, LOXs from all organisms can be used to oxygenate all polyunsaturated fatty acids, including AA, ALA, OA, and LA, to form various positional-specific hydroperoxy fatty acids, including new-type hydroperoxy fatty acids, because LOXs exhibit broad substrate specificity. As an example, bacterial LOXs can be used to oxygenate ALA. These new positional-specific hydroperoxy fatty acids can be metabolized to

form new leukotrienes, lipoxins, jasmonic acids, green leaf volatiles, and lactones. The LOX superfamily exhibits diverse regiospecificity; Table 1 shows the various oxygenation positions on polyunsaturated fatty acid substrates. The regiospecificity of LOX can be changed by substituting several amino acids for substrate-binding residues. Many studies have examined changes in LOX regiospecificity by using protein engineering methods based on enzyme structure to conduct the oxygenation at tailored positions on the substrate. The ability to construct tailor-made processes will provide novel hydroxy and hydroperoxy fatty acids with desired properties. Acyl-CoA oxidase 2 catalyzes the β-oxidation from C18 hydroxy fatty acid to C10 hydroxy fatty acid (Romero-Guido et al., 2011), and lactonase reversibly catalyzes lactonization of hydroxy fatty acid (Martin et al., 2009). Thus, lactone-producing metabolically engineered cells can be developed by introducing foreign positionalspecific LOX, acyl-CoA oxidase 2, and lactonase genes. Introduction of positional-specific LOX, allene oxide cyclase, reductase, and acylCoA oxidase 2 genes into host may result in the production of jasmonic acids and introduction of positional-specific LOX, allene oxide cyclase, reductase, and two hydroxylases genes into host may result in the production of prostaglandins (Fig. 1). The metabolically engineered cells containing diverse LOXs and foreign signaling compound-synthesizing genes will be potential cell factories for producing various prostaglandins, jasmonic acids, green leaf volatiles, and lactones. These signaling compounds can be applied to evaluate their biological and pharmaceutical activities, related to the expression of genes and regulation of signal pathways involved in diseases. Acknowledgment This work was supported by the Konkuk University. References Acosta IF, Laparra H, Romero SP, Schmelz E, Hamberg M, Mottinger JP, et al. tasselseed1 is a lipoxygenase affecting jasmonic acid signaling in sex determination of maize. Science 2009;323:262–5. Allmann S, Baldwin IT. Insects betray themselves in nature to predators by rapid isomerization of green leaf volatiles. Science 2010;329:1075–8. Allmann S, Halitschke R, Schuurink RC, Baldwin IT. Oxylipin channelling in Nicotiana attenuata: lipoxygenase 2 supplies substrates for green leaf volatile production. Plant Cell Environ 2010;33:2028–40. Andre E, Hou KW. The presence of a lipid oxidase in soybean glycine soya. Acad Sci (Paris) 1932;194:645–7. Andreou A, Feussner I. Lipoxygenases — structure and reaction mechanism. Phytochemistry 2009;70:1504–10. Andreou AZ, Vanko M, Bezakova L, Feussner I. Properties of a mini 9R-lipoxygenase from Nostoc sp. PCC 7120 and its mutant forms. Phytochemistry 2008;69:1832–7. Andreou A, Brodhun F, Feussner I. Biosynthesis of oxylipins in non-mammals. Prog Lipid Res 2009;48:148–70. Andreou A, Gobel C, Hamberg M, Feussner I. A bisallylic mini-lipoxygenase from cyanobacterium Cyanothece sp. that has an iron as cofactor. J Biol Chem 2010;285: 14178–86. Bannenberg G, Martinez M, Hamberg M, Castresana C. Diversity of the enzymatic activity in the lipoxygenase gene family of Arabidopsis thaliana. Lipids 2009;44:85–95. Bisakowski B, Atwal AS, Kermasha S. Characterization of lipoxygenase activity from a partially purified enzymic extract from Morchella esculenta. Process Biochem 2000;36:1–7. Brash AR, Baertschi SW, Ingram CD, Harris TM. On non-cyclooxygenase prostaglandin synthesis in the sea whip coral, Plexaura homomalla: an 8(R)-lipoxygenase pathway leads to formation of an alpha-ketol and a racemic prostanoid. J Biol Chem 1987;262:15829–39. Brash AR, Boeglin WE, Chang MS, Shieh BH. Purification and molecular cloning of an 8R-lipoxygenase from the coral Plexaura homomalla reveal the related primary structures of R- and S-lipoxygenases. J Biol Chem 1996;271:20949–57. Brodhun F, Feussner I. Oxylipins in fungi. FEBS J 2011;278:1047–63. Buchhaupt M, Guder JC, Etschmann MM, Schrader J. Synthesis of green note aroma compounds by biotransformation of fatty acids using yeast cells coexpressing lipoxygenase and hydroperoxide lyase. Appl Microbiol Biotechnol 2012;93: 159–68. Burridge S. Cancer: lipoxygenase makes a leaky tumour. Nat Rev Drug Discov 2011;10: 414. Caballero J, Fernandez M, Coll D. Quantitative structure–activity relationship of organosulphur compounds as soybean 15-lipoxygenase inhibitors using CoMFA and CoMSIA. Chem Biol Drug Des 2010;76:511–7.

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