Lipoxygenases: Occurrence, Functions, Catalysis, and Acquisition of Substrate

hydroxyeicosatetraenoic acid hydroperoxyeicosatetraenoic acid lipoxygenase(s) peroxisome proliferator-activated receptor Src homology 3 domain 5-lipoxygenase-activating protein Lipoxygenase reactions may initiate the synthesis of a signaling molecule or be involved in inducing structural or metabolic changes in the cell. For signaling, synthesis of a single fatty acid hydroperoxide is required. For inducing structural changes, synthesis of a particular product may not be so important as the ability to induce what amounts to an enzyme-catalyzed lipid peroxidation. Reflecting these different functions are lipoxygenases with different characteristics in catalysis. There are enzymes that tightly control the reaction with molecular oxygen and others that form mixed products and permit the release of free radicals. In this review the diversity of lipoxygenase expression will be highlighted and the several facets of lipoxygenase function considered, concluding with a discussion of issues related to the acquisition of substrate in a cellular environment. Lipoxygenases are found widely in plants, fungi, and animals (1Grechkin A. Prog. Lipid Res. 1998; 37: 317-352Crossref PubMed Scopus (269) Google Scholar, 2Gerwick W.H. Biochim. Biophys. Acta. 1994; 1211: 243-255Crossref PubMed Scopus (93) Google Scholar, 3De Petrocellis L. Di Marzo V. Prostaglandins Leukotrienes Essent. Fatty Acids. 1994; 51: 215-229Abstract Full Text PDF PubMed Scopus (49) Google Scholar, 4Funk C.D. Biochim. Biophys. Acta. 1996; 1304: 65-84Crossref PubMed Scopus (238) Google Scholar, 5Yamamoto S. Suzuki H. Ueda N. Prog. Lipid Res. 1997; 36: 23-41Crossref PubMed Scopus (101) Google Scholar). The suitable substrates are polyunsaturated fatty acids containing a series of cis double bonds. These are the essential fatty acids in humans. These substrates are not present in most bacteria (cyanobacteria and some marine species excepted (6Gerwick W.H. Bernart M.W. Attaway D.H. Zaborsky O.R. Marine Bio/Technology, Volume I: Pharmaceutical and Bioactive Natural Products. Plenum Publishing Corp., New York1993: 101-152Google Scholar, 7Watanabe K. Ishikawa C. Ohtsuka I. Kamata M. Tomita M. Yazawa K. Muramatsu H. Lipids. 1997; 32: 975-978Crossref PubMed Scopus (22) Google Scholar)), and yeast also lack the necessary desaturases for their synthesis. In accord with this absence of substrate, there is no lipoxygenase in the yeast genome (Saccharomyces cerevisiae), and lipoxygenases are also absent from typical prokaryotes. There is no definitive account of a lipoxygenase in insects, although a typical arachidonic acid-derived lipoxygenase product (hydroxyeicosatetraenoic acid (HETE)1) is identified in the primitive insect Thermobia domestica (8Ragab A. Durand J. Bitsch C. Chap H. Rigaud M. Insect Biochem. 1991; 21: 321-326Crossref Scopus (13) Google Scholar). There is a lipoxygenase in the unicellular Chlorella (9Zimmerman D.C. Lipids. 1973; 8: 264-266Crossref PubMed Scopus (56) Google Scholar) and a partial lipoxygenase cDNA sequence in the data bases from the slime mold Dictyostelium discoideum. Higher plants contain multiple lipoxygenases with at least eight identified in soybean, Glycine max. In the mouse there are seven genes that express lipoxygenase proteins, and five homologues (and an expressed pseudogene) are characterized in humans (10Krieg P. Kinzig A. Heidt M. Marks F. Fürstenberger G. Biochim. Biophys. Acta. 1998; 1391: 7-12Crossref PubMed Scopus (51) Google Scholar, 11Boeglin W.E. Kim R.B. Brash A.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6744-6749Crossref PubMed Scopus (148) Google Scholar, 12Sun D. Elsea S.H. Patel P.I. Funk C.D. Cytogenet. Cell Genet. 1998; 81: 79-82Crossref PubMed Scopus (21) Google Scholar). Lipoxygenases are expressed in some plant and animal tissues in high levels; they constitute a few percent of the protein in soybeans, and a 15-lipoxygenase (15-LOX) represents one of the main proteins besides hemoglobin in rabbit reticulocytes during anemia (13Rapoport S.M. Schewe T. Wiesner R. Halangk W. Ludwig P. Janicke-Hohne M. Tannert C. Klatt D. Eur. J. Biochem. 1979; 96: 545-561Crossref PubMed Scopus (230) Google Scholar). Lipoxygenase expression may also be more subtle and low level, as in the cell-specific expression of specific isozymes in soybean leaves (14Stephenson L.C. Bunker T.W. Dubbs W.E. Grimes H.D. Plant Physiol. 1998; 116: 923-933Crossref PubMed Scopus (38) Google Scholar) or the discrete expression of distinct lipoxygenases in mammalian skin (e.g. Ref. 15Jisaka M. Kim R.B. Nanney L.B. Boeglin W.E. Brash A.R. J. Biol. Chem. 1997; 272: 24410-24416Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). The phylogenetic tree separates the plant and animal enzymes and forms several subgroups within each kingdom (Fig.1). The formation of a particular lipoxygenase product is not necessarily associated with closely related sequences. For example, the soybean L-1 enzyme, a 15-LOX, has only 25% identity to any mammalian 15-lipoxygenase, and the two human 15-LOX share only 35% identity with each other. By contrast, the close functional homologues across species, forming distinct subgroups, share 70–95% sequence identity. In practical usage this is based on the specificity of the enzyme acting on its substrate, and although this can become slightly awkward, it conveys a simple and useful message. 12-LOX oxygenates arachidonic acid at carbon-12, and when necessary, the stereoconfiguration is specified (12 R-LOX or 12 S-LOX (Scheme FS1)). The differing chain lengths of the most common substrates of plants (linoleate, linolenate, 18-carbon) and animals (arachidonate, 20-carbon) result in a plant 13-LOX corresponding to a mammalian 15-LOX; these particular lipoxygenases "count" the substrate carbons from the tail end of the chain, and both react oxygen at the ω-6 position. Complications can arise, for example, when there is more than one 12-LOX in the same species. To get around this problem, currently the mammalian 12-lipoxygenases are named after the prototypical tissues of their occurrence (hence, the platelet, leukocyte, or epidermal type of 12-LOX (5Yamamoto S. Suzuki H. Ueda N. Prog. Lipid Res. 1997; 36: 23-41Crossref PubMed Scopus (101) Google Scholar)). These are distinct enzymes by sequence, catalytic activities, and function. Some lipoxygenases may form a mixture of products, e.g. the mammalian reticulocyte type of lipoxygenase catalyzes C-12 and C-15 oxygenation, with the relative proportions varying among species. In rabbits and humans the major product is 15-HPETE, and hence the enzyme is designated a 15-LOX. The most closely related enzyme in the rat, mouse, pig, and cow is the leukocyte type of 12-LOX, an enzyme that catalyzes mainly C-12 oxygenation with some reaction also at C-15 (5Yamamoto S. Suzuki H. Ueda N. Prog. Lipid Res. 1997; 36: 23-41Crossref PubMed Scopus (101) Google Scholar). This is usually characterized by synthesis of a single specific hydroperoxide from free fatty acid substrate (Fig.2). Two subcategories are recognized with the lipoxygenase product either an intermediate or end product in the metabolic pathway. Some examples are jasmonic acid and aldehyde biosynthesis in plant signaling (1Grechkin A. Prog. Lipid Res. 1998; 37: 317-352Crossref PubMed Scopus (269) Google Scholar) and leukotriene or lipoxin synthesis in vertebrate animals (16Samuelsson B. Adv. Exp. Med. Biol. 1997; 433: 1-7Crossref PubMed Scopus (9) Google Scholar,17Serhan C.N. Prostaglandins. 1997; 53: 107-137Crossref PubMed Scopus (225) Google Scholar). In human beings, activation of the 5-LOX of leukocytes produces the leukotrienes and these lipid-peptide conjugates and dihydroxyeicosanoids provoke bronchoconstriction and inflammation. Current medications for asthma include 5-LOX inhibitors and leukotriene receptor antagonists (18Drazen J.M. Israel E. O'Byrne P.M. N. Engl. J. Med. 1999; 340: 197-206Crossref PubMed Scopus (775) Google Scholar). Synthesis of these end products represents the best recognized and most firmly established functions of lipoxygenases. An example is 12-HETE synthesis by the platelet 12 S-LOX. Numerous biological activities are ascribed to individual HETEs and HPETEs, and the weight of evidence now suggests these products act as discrete signaling molecules. Here the actions are mediated at the cell surface on receptors or channels, and the HETE bioactivity is evident in the nanomolar range. In modulating neurotransmission, 12-HETE and its derivatives act fast (19Piomelli D. Volterra A. Dale N. Siegelbaum S.A. Kandel E.R. Schwartz J.H. Belardetti F. Nature. 1987; 328: 38-43Crossref PubMed Scopus (531) Google Scholar). The 5-HETE oxidation product 5-oxo-eicosatetraenoic acid has instant receptor-mediated actions on calcium fluxes (20O'Flaherty J.T. Taylor J.S. Thomas M.J. J. Biol. Chem. 1998; 273: 32535-32541Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar), and the potent effects of 12 S-HETE on cell adhesion, an activity linked to metastasis in prostate carcinoma (21Tang D.G. Honn K.V. Ann. N. Y. Acad. Sci. 1994; 744: 199-215Crossref PubMed Scopus (49) Google Scholar), are considered to act through cell surface signaling and activation of protein kinase C (22Liu B. Maher R.J. Hannun Y.A. Porter A.T. Honn K.V. J. Natl. Cancer Inst. 1994; 86: 1145-1150Crossref PubMed Scopus (105) Google Scholar). There is evidence of a G-protein-coupled 12-HETE receptor in melanoma cells (23Liu B. Khan W.A. Hannun Y.A. Timar J. Taylor J.D. Lundy S. Butovich I. Honn K.V. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9323-9327Crossref PubMed Scopus (101) Google Scholar). It is striking how the platelet 12-LOX keeps making product for hours (24Hwang D.H. Lipids. 1982; 17: 845-847Crossref PubMed Scopus (16) Google Scholar), whereas the platelet cyclooxygenase generates a short burst of products and is inactivated. An inference is that 12-HETE may modulate longer term events rather than fast responses such as platelet aggregation. Effects on cell differentiation or survival are examples (25Yu K. Bayona W. Kallen C.B. Harding H.P. Ravera C.P. McMahon G. Brown M. Lazar M.A. J. Biol. Chem. 1995; 270: 23975-23983Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 26Tang D.G. Chen Y.Q. Honn K.V. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 5241-5246Crossref PubMed Scopus (328) Google Scholar). The search for natural ligands for the orphan nuclear receptors has produced some provocative data on activities of the HETEs (25Yu K. Bayona W. Kallen C.B. Harding H.P. Ravera C.P. McMahon G. Brown M. Lazar M.A. J. Biol. Chem. 1995; 270: 23975-23983Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar, 27Sørensen H.N. Treuter E. Gustafsson J.-A. Vitam. Horm. 1998; 54: 121-166Crossref PubMed Scopus (52) Google Scholar). Yet, only 8 S-HETE has submicromolar activity in PPAR-reporter assays (25Yu K. Bayona W. Kallen C.B. Harding H.P. Ravera C.P. McMahon G. Brown M. Lazar M.A. J. Biol. Chem. 1995; 270: 23975-23983Abstract Full Text Full Text PDF PubMed Scopus (646) Google Scholar), and 8 S-HETE is known as a natural product only in mouse skin (28Fürstenberger G. Hagedorn H. Jacobi T. Besemfelder E. Stephan M. Lehmann W.D. Marks F. J. Biol. Chem. 1991; 266: 15738-15745Abstract Full Text PDF PubMed Google Scholar). Linoleate derivatives and other HETEs are significantly weaker PPAR ligands, although it is argued that this has potential physiological significance in relation to oxidation of low density lipoprotein and the initiation of atherosclerosis (29Nagy L. Tontonoz P. Alvarez J.G.A. Chen H. Evans R.M. Cell. 1998; 93: 229-240Abstract Full Text Full Text PDF PubMed Scopus (1612) Google Scholar); certainly, high concentrations of hydroxylinoleates can accumulate (30Jira W. Spiteller G. Carson W. Schramm A. Chem. Phys. Lipids. 1998; 91: 1-11Crossref PubMed Scopus (118) Google Scholar). Typically this is associated with metabolism of esterified substrate and often produces a mixture of hydroperoxy products (Fig. 2). Here, the objective is to induce physical changes in the cell or change the peroxide tone, and the structure of the hydroperoxy product is not so important as its effects in (a) perturbing membrane structure and (b) provoking secondary oxygenations (enzyme-catalyzed lipid peroxidation). The concept that a lipoxygenase could peroxidize membrane lipids and thus help induce a series of programmed structural changes in a cell was originally developed around the mammalian reticulocyte 15-LOX and its potential role in red cell maturation (31Rapoport S.M. Schewe T. Biochim. Biophys. Acta. 1986; 864: 471-495Crossref PubMed Scopus (117) Google Scholar). Keratinocyte maturation and lens epithelial cell development offer similar possibilities (32Schewe T. Kühn H. Trends Biochem. Sci. 1991; 16: 369-373Abstract Full Text PDF PubMed Scopus (63) Google Scholar). Subsequently, the same 15-LOX enzyme has been implicated in the oxidation of low density lipoprotein, a key event in the initiation of atherosclerosis (33Feinmark S.J. Cornicelli J.A. Biochem. Pharmacol. 1997; 54: 953-959Crossref PubMed Scopus (39) Google Scholar). Similar concepts have evolved independently in the plant literature where a role for lipoxygenases in plant senescence is proposed (e.g. Ref. 34Hung K.T. Kao C.H. Bot. Bull. Acad. Sin. 1997; 38: 85-89Google Scholar). An issue here, and in ascribing functions to other lipoxygenases, is the fact that gene knockout experiments in mice indicate no obvious problems in development or cell differentiation (4Funk C.D. Biochim. Biophys. Acta. 1996; 1304: 65-84Crossref PubMed Scopus (238) Google Scholar). Similarly, transgenic plants lacking one or several lipoxygenases exhibit subtle changes (35Narvel J.M. Fehr W.R. Welke G.A. Crop Sci. 1998; 38: 926-928Crossref Scopus (26) Google Scholar). The lipoxygenases modulate events, and their role may become evident only under physiological or pathological stress (4Funk C.D. Biochim. Biophys. Acta. 1996; 1304: 65-84Crossref PubMed Scopus (238) Google Scholar). As mentioned earlier under "Nomenclature," the human reticulocyte type of 15-LOX (15-LOX-1) and its animal counterparts form a mixture of 12-HPETE and 15-HPETE. Is this imperfect catalysis by design? It is hard to imagine that the objective is to form mainly one product and a small amount of another. The imperfect fit in the active site and the resulting mobility of the substrate during catalysis might be designed to promote release of free radical intermediates. This accords with the view that the reticulocyte type of 15-LOX functions as a catalyst of lipid peroxidation. It is also notable that this class of lipoxygenase functions for only a minute or two before a turnover-related inactivation kills the enzyme (36Hada T. Ueda N. Takahashi Y. Yamamoto S. Biochim. Biophys. Acta. 1991; 1083: 89-93Crossref PubMed Scopus (66) Google Scholar). By contrast, lipoxygenases that cleanly catalyze formation of a single product (e.g. the platelet type of 12-LOX, the mouse 8-LOX, and the human 15-LOX-2) can keep running near a linear rate for an hour or more (24Hwang D.H. Lipids. 1982; 17: 845-847Crossref PubMed Scopus (16) Google Scholar, 28Fürstenberger G. Hagedorn H. Jacobi T. Besemfelder E. Stephan M. Lehmann W.D. Marks F. J. Biol. Chem. 1991; 266: 15738-15745Abstract Full Text PDF PubMed Google Scholar, 36Hada T. Ueda N. Takahashi Y. Yamamoto S. Biochim. Biophys. Acta. 1991; 1083: 89-93Crossref PubMed Scopus (66) Google Scholar). Lipoxygenase-catalyzed oxygenation of unsaturated fatty acids esterified in triglycerides is implicated in the germination process in oil-seed plants (37Feussner I. Kühn H. Wasternack C. FEBS Lett. 1997; 406: 1-5Crossref PubMed Scopus (41) Google Scholar). After conversion specifically to the 13-hydroperoxy esters, the fatty acids become available for β-oxidation and utilization as a fuel source for the developing embryo. An equivalent function has not been ascribed in animal biology, yet this peroxidation of lipid stores serves as a potential model to rationalize, for example, the high lipoxygenase content of certain animal oocytes, which also carry stores for embryo development (e.g. Ref. 38Hawkins D.J. Brash A.R. J. Biol. Chem. 1987; 262: 7629-7634Abstract Full Text PDF PubMed Google Scholar). Lipoxygenase proteins have a single polypeptide chain with a molecular mass of ∼75–80 kDa in animals and ∼94–104 kDa in plants. The proteins have a N-terminal β-barrel domain (Fig. 3, top panel, white, and discussed later under "Acquisition of Substrate") and a larger catalytic domain containing a single atom of non-heme iron (Fig. 3). The metal is liganded to conserved histidines and to the carboxyl group of a conserved isoleucine at the C terminus of the protein (Fig. 3). As the iron is non-heme, lipoxygenases appear virtually colorless to the eye. The enzymes are usually in the ferrous (inactive) form when isolated. Oxidation to the active ferric enzyme is required for catalysis (SchemeFS2).Figure FS2View Large Image Figure ViewerDownload Hi-res image Download (PPT) There are four available crystal structures, of which three are of the arachidonate 15-lipoxygenases, soybean L-1, and rabbit reticulocyte 15-LOX (39Boyington J.C. Gaffney B.J. Amzel L.M. Science. 1993; 260: 1482-1486Crossref PubMed Scopus (460) Google Scholar, 40Minor W. Steczko J. Stec B. Otwinowski Z. Bolin J.T. Walter R. Axelrod B. Biochemistry. 1996; 35: 10687-10701Crossref PubMed Scopus (396) Google Scholar, 41Gillmor S.A. Villaseñor A. Fletterick R. Sigal E. Browner M.F. Nat. Struct. Biol. 1997; 4: 1003-1009Crossref PubMed Scopus (399) Google Scholar), and the fourth, soybean L-3, is a catalyst of nonspecific peroxidation (42Skrzypczak-Jankun E. Amzel L.M. Kroa B.A. Funk M.O.J. Proteins Struct. Funct. Genet. 1997; 29: 15-31Crossref PubMed Scopus (150) Google Scholar). There is no consensus on how substrate gains access to the metal center or any definitive information on substrate binding. The reticulocyte 15-LOX structure has a bound inhibitor lying opposite His-3 as it is designated in Fig. 3 (see legend), and its position helps identify a likely substrate binding site (41Gillmor S.A. Villaseñor A. Fletterick R. Sigal E. Browner M.F. Nat. Struct. Biol. 1997; 4: 1003-1009Crossref PubMed Scopus (399) Google Scholar). The apparent access channel for arachidonic acid in this model opens onto the top surface of the protein as viewed in Fig. 3. This route is by in the corresponding crystal of the soybean L-1 and The soybean enzymes both have a to the of the iron as in Fig. 3 and an to the protein surface on the There is a more route to the surface of the In the structure and the β-barrel domain (42Skrzypczak-Jankun E. Amzel L.M. Kroa B.A. Funk M.O.J. Proteins Struct. Funct. Genet. 1997; 29: 15-31Crossref PubMed Scopus (150) Google Scholar). three are of the ferrous (inactive) form of the It is likely that during the active form that will result in a model of catalysis. The soybean L-1 is a 15-lipoxygenase, at low enzyme forms only from arachidonic It this oxygenation cleanly with other soybean isozymes or the mammalian reticulocyte type of 15-LOX. L-1 to catalyze specific and 8 The 15-HPETE, is at a rate by of enzyme to the specific double oxygenation products, and 8 H. J. Biochim. Biophys. Acta. PubMed Scopus Google Scholar). The important is that the same enzyme, and the same active is to catalyze and 8 lipoxygenase in the active site is one of the to control of the oxygenation reaction The best known plant and animal lipoxygenases form products with now that lipoxygenases forming the image products are also found among Petrocellis L. Di Marzo V. Prostaglandins Leukotrienes Essent. Fatty Acids. 1994; 51: 215-229Abstract Full Text PDF PubMed Scopus (49) Google Scholar), plants W.H. Biochim. Biophys. Acta. 1994; 1211: 243-255Crossref PubMed Scopus (93) Google Scholar), and in humans W.E. Kim R.B. Brash A.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6744-6749Crossref PubMed Scopus (148) Google Scholar). contain the same conserved iron ligands and other sequence common to plant or animal A.R. Boeglin W.E. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). There are no known or that account for the opposite and a subtle change in reaction specificity be of the image and acids have a and 8 Biochemistry. 1996; 35: PubMed Scopus Google Scholar) and will be and in at the typical physiological of these the free fatty acids by the of a will have to the membrane by with a The free acid might be to with its tail in the and its more carboxyl or in the or associated with the of These substrates are not necessarily available for lipoxygenase In a of the oxygenation of free and acids it was found that the soybean L-1 and isozymes not free acid substrates mixed with biological In the same the enzyme not the membrane M. G.A. Biochim. Biophys. Acta. 1994; PubMed Scopus Google Scholar). By contrast, activity of the reticulocyte type of mammalian 15-LOX on free acid substrates is by with R. K. D. T. G. Kühn H. 1998; 91: PubMed Google Scholar), and this enzyme will also esterified substrates for (31Rapoport S.M. Schewe T. Biochim. Biophys. Acta. 1986; 864: 471-495Crossref PubMed Scopus (117) Google Scholar). potential to involved in substrate acquisition from that the conserved β-barrel domain of lipoxygenases homology to a similar domain at the C terminus of the mammalian (41Gillmor S.A. Villaseñor A. Fletterick R. Sigal E. Browner M.F. Nat. Struct. Biol. 1997; 4: 1003-1009Crossref PubMed Scopus (399) Google Scholar). most lipoxygenases, the are yet access to substrate in a membrane environment. The lipoprotein β-barrel functions in the acquisition of substrate through receptor and by with lipoprotein (41Gillmor S.A. Villaseñor A. Fletterick R. Sigal E. Browner M.F. Nat. Struct. Biol. 1997; 4: 1003-1009Crossref PubMed Scopus (399) Google Scholar). 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A. 1999; 96: PubMed Scopus Google Scholar). to be protein with the equivalent function in substrate or a for has been found for any other fatty acid other mammalian lipoxygenases have the consensus binding and there is evidence of membrane on cell The of a lipoxygenase and its ability to on the fatty acid the two cis double of and issues related to catalysis and reaction C. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). It to be this represents a class of enzyme or is related to the lipoxygenase the of a plant related in sequence to mammalian cyclooxygenase will in the metabolism of the typical lipoxygenase and acids A. C. Plant Cell. 1998; PubMed Scopus Google Scholar). The protein in a issues of and the effects of a enzyme on peroxide activation of a lipoxygenase R. N. Brash A.R. Science. 1997; PubMed Scopus Google Scholar). the of in mammalian may more in these enzymes and their potential in the of lipoxygenase (10Krieg P. Kinzig A. Heidt M. Marks F. Fürstenberger G. Biochim. Biophys. Acta. 1998; 1391: 7-12Crossref PubMed Scopus (51) Google Scholar, 11Boeglin W.E. Kim R.B. Brash A.R. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 6744-6749Crossref PubMed Scopus (148) Google Scholar, D. M. Chen H. Elsea S.H. Patel P.I. Funk C.D. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus (66) Google Scholar). to and for and for help with the