Lipoxygenases (E.C. 1.13.11.-)

Overview: The lipoxygenases (LOXs) are a structurally related family (ENSFM00250000000705) of non-heme iron dioxygenases that function in the production, and in some cases metabolism, of fatty acid hydroperoxides. In humans there are five LOXs, the 5S-(arachidonate : oxygen 5-oxidoreductase), 12R-(arachidonate 12-lipoxygenase, 12R-type), 12S-(arachidonate : oxygen 12-oxidoreductase), and two distinct 15s-(arachidonate : oxygen 15-oxidoreductase) LOXs that oxygenate arachidonic acid in different positions along the carbon chain and form the corresponding 5S-, 12S-, 12R-, or 15S-hydroperoxides, respectively. The sixth LOX member, epidermal lipoxygenase 3 (E-LOX), metabolises the product from the 12R-lipoxygenase (12R-HPETE) to a specific epoxyalcohol compound (Yu et al., 2003). Some general LOX inhibitors are NDGA and esculetin.

Nomenclature	5-LOX	12R-LOX	12S-LOX
E.C.	1.13.11.34	1.13.11.-	1.13.11.31
Other names	ALOX5	ALOX12B, epidermis-type lipoxygenase 12	ALOX12, platelet-type 12-lipoxygenase
Ensembl ID	ENSG00000012779	ENSG00000179477	ENSG00000108839
Substrates	Arachidonic acid	Methyl arachidonate	Arachidonic acid
Activators	FLAP	–	–
Selective inhibitors	Zileuton, CJ13610 (Fischer et al., 2004)	–	–

The crystal structure of FLAP has been described (Ferguson et al., 2007).

Nomenclature	15-LOX-1	15-LOX-2	E-LOX
E.C.	1.13.11.33	1.13.11.33	1.13.11.-
Other names	ALOX15, arachidonate ω-6 lipoxygenase	ALOX15B	Epidermis type LOX 3
Ensembl ID	ENSG00000161905	ENSG00000179593	ENSG00000179148
Substrates	Linoleic acid, arachidonic acid	Arachidonic acid	12R-HPETE

An 8-LOX (EC 1.13.11.40, arachidonate : oxygen 8-oxidoreductase) may be the mouse orthologue of 15-LOX-2 (Furstenberger et al., 2002). Zileuton and caffeic acid are used as 5-lipoxygenase inhibitors, while baicalein and CDC are 12-lipoxygenase inhibitors. The specificity of these inhibitors has not been rigorously assessed with all LOX forms: baicalein, along with other flavonoids, such as fisetin and luteolin, also inhibits 15-LOX-1 (Sadik et al., 2003).

Glossary

Abbreviations:

CDC

cinnamyl-3,4-dihydroxy-α-cyanocinnamate

CJ13610

1-carboxamido-1-(3-S-[4-{2-methylimididazole}-thiophenyl])-4-cyclopentylether

esculetin

6,7-dihydroxycoumarin

12R-HPETE

12R-hydroperoxyeicosatetraenoic acid

FLAP

5-lipoxygenase-activating protein, also known as MK-886-binding protein (ENSG00000132965)

NDGA

nordihydroguaiaretic acid

Further Reading

Chawengsub Y, Gauthier KM, Campbell WB (2009). Role of arachidonic acid lipoxygenase metabolites in the regulation of vascular tone. Am J Physiol Heart Circ Physiol297: H495–H507.

Evans JF, Ferguson AD, Mosley RT, Hutchinson JH (2008). What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases. Trends Pharmacol Sci29: 72–78.

Feltenmark S, Gautam N, Brunnstrom A, Griffiths W, Backman L, Edenius C et al. (2008). Eoxins are proinflammatory arachidonic acid metabolites produced via the 15-lipoxygenase-1 pathway in human eosinophils and mast cells. Proc Natl Acad Sci USA105: 680–685.

Furstenberger G, Epp N, Eckl KM, Hennies HC, Jorgensen C, Hallenborg P et al. (2007). Role of epidermis-type lipoxygenases for skin barrier function and adipocyte differentiation. Prostaglandins Other Lipid Mediat82: 128–134.

Geiger EV, Doehring A, Kirchhof A, Lotsch J (2009). Functional variants of the human 5-lipoxygenase gene and their genetic diagnosis. Prostaglandins Leukot Essent Fatty Acids80: 255–262.

Murphy RC, Gijón MA (2007). Biosynthesis and metabolism of leukotrienes. Biochem J405: 379–395.

Radmark O, Samuelsson B (2007). 5-lipoxygenase: regulation and possible involvement in atherosclerosis. Prostaglandins Other Lipid Mediat83: 162–174.

Radmark O, Samuelsson B (2009). 5-Lipoxygenase: mechanisms of regulation. J Lipid Res50(Suppl.): S40–S45.

Radmark O, Werz O, Steinhilber D, Samuelsson B (2007). 5-Lipoxygenase: regulation of expression and enzyme activity. Trends Biochem Sci32: 332–341.

Rubin P, Mollison KW (2007). Pharmacotherapy of diseases mediated by 5-lipoxygenase pathway eicosanoids. Prostaglandins Other Lipid Mediat83: 188–197.