Mammalian lipoxygenases and their biological relevance

Abstract

Lipoxygenases (LOXs) form a heterogeneous class of lipid peroxidizing enzymes, which have been implicated not only in cell proliferation and differentiation but also in the pathogenesis of various diseases with major public health relevance. As other fatty acid dioxygenases LOXs oxidize polyunsaturated fatty acids to their corresponding hydroperoxy derivatives, which are further transformed to bioactive lipid mediators (eicosanoids and related substances). On the other hand, lipoxygenases are key players in the regulation of the cellular redox homeostasis, which is an important element in gene expression regulation. Although the first mammalian lipoxygenases were discovered 40 years ago and although the enzymes have been well characterized with respect to their structural and functional properties the biological roles of the different lipoxygenase isoforms are not completely understood. This review is aimed at summarizing the current knowledge on the physiological roles of different mammalian LOX-isoforms and their patho-physiological function in inflammatory, metabolic, hyperproliferative, neurodegenerative and infectious disorders. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".

Keywords: Atherosclerosis; Cancer; Eicosanoid; Infection; Inflammation; Stroke.

Fig. 1. Simplified scheme of the lipoxygenase reaction

LOXs convert polyenoic fatty acids containing at least one 1,4-pentadiene system to their corresponding hydroperoxy derivatives. Atmospheric oxygen serves as second substrate.

Fig. 2. Biological function of lipoxygenase

Lipoxygenases may exhibit their biological functionality via three different mechanistic scenarios. i) Formation of bioactive lipid mediators, ii) Structural modification of complex lipid-protein assemblies. iii) Modification of the cellular redox homeostasis, which alters the gene expression pattern.

Fig. 3. Distribution of lipoxygenases in the kingdoms of terrestrial life

Lipoxygenase genes have been detected in two (bacteria, eukarya) of the three kingdoms of terrestrial life. Although LOX-like sequences have also been described in archaea, no functional LOX enzyme has been reported to occur.

Fig. 4. Crystal structure of the stabilized version of human ALOX5

The N-terminal β-barrel domain is shown in yellow, the flexible inter-domain linker (D113-L118) in magenta, the C-terminal catalytic domain in green and the iron liganding residues in red. The residues mutated in wild-type ALOX5 to get the stabilized version of the enzyme suitable for crystallization are indicated in blue. The image was constructed from the X-ray diffraction data using the PyMol software package.

Fig. 5. Classification and structure of leukotrienes

A) Leukotriene biosynthesis, B) Structure of leukotrienes.

Fig. 6. Co-localization of ALOX15 with the microglial/macrophage marker CD163

Depending on disease state, various cell types can show increased ALOX15. Shown here in A and B are two examples of brain tissue from infants with periventricular leukomalacia, where ALOX15 (12/15-LOX) co-localizes with the microglial/macrophage marker CD163, suggesting a role in disease pathology. ALOX15 in these brains was also increased in oligodendrocytes (courtesy of Dr. Robin Haynes, Children’s Hospital Boston)

Fig. 7. Principal modes of action of lipoxygenase inhibitors

NDGA - nordihydroguaiaretic acid, HODE - hydroxy octadecadienoic acid, ETYA - 5,8,11,14-eicosatetraynoic acid, ODYA - 9,12-octadecadiynoic acid, OPP - 4-(2-oxapentadeca-4-yne)phenylpropanoic acid,