Lipoxin biosynthesis by human lipoxygenases
Physical and Biological Sciences
Molecular, Cell, and Developmental Biology
Lipoxygenases (LOXs) are a family of enzymes that catalyze the oxidation of arachadonic acid (AA) and other polyunsaturated fatty acid (PUFA) substrates in the cell. Oxidized PUFAs have far-reaching effects in the human body, including resolution (reduction) of inflammation associated with cardiovascular disease, regulation of macrophages ability to respond appropriately during an innate immune response, and inhibition of the proliferation of prostate carcinoma (cancer) cells. Lipoxins are tri-hydroxylated (oxygenated) derivatives of AA that are made through catalytic pathways involving multiple LOXs. Lipoxins have been shown to exhibit many anti-inflammatory bioactivities and to promote host immune defense. Though there have been many studies regarding the role of LXs in inflammation resolution, there has not been a comprehensive investigation into the complex biosynthetic pathway of LXs. In this investigation we have used four human LOXs (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2) and have tested their activity against multiple PUFA substrates. LX formation was observed only with specific derivatives of AA, suggesting certain pathways are more facile than others. In addition, we observed a critical intermediate product – 5,15-diHpETE (AA that has been oxidized at carbon 5 and 15) – that is essential for LX biosynthesis. In addition, we discovered that the 15-LOX-2 enzyme is also capable of LX formation, a function that had previously been unknown.
