Recent Advances on 5‐Lipoxygenase Biochemistry

Abstract

5‐Lipoxygenase (5‐LOX) catalyses two steps in the biosynthesis of leukotrienes (LTs), lipid mediators of inflammation derived from arachidonic acid. LTs function in normal host defence, and have pathophysiological roles in chronic inflammatory diseases, as asthma and atherosclerosis. Also, possible effects of 5‐LOX products in relation to tumorigenesis have been described. 5‐LOX is also involved in the biosynthesis of anti‐inflammatory/pro‐resolving lipoxins. 5‐LOX is mainly expressed in myeloid and lymphoid cells and its expression is upregulated during cell differentiation. Cellular 5‐LOX activity is regulated in a complex manner and depends on cellular localisation, phosphorylation, the intracellular calcium concentration and the redox status of the cell. Thus, insight regarding the biochemistry of 5‐LOX is relevant for better understanding of normal physiology, and for development of pharmacotherapy.

Key Concepts:

  • Lipoxygenases oxygenate polyunsaturated fatty acids.

  • 5‐LOX produces 5‐HPETE, leukotrienes and together with other dioxygenases lipoxins.

  • The regulatory C2‐like domain binds Ca2+, diacylglycerols and phosphatidylcholine and regulates the activity of the catalytic domain.

  • 5‐LOX interacts with various proteins such as FLAP, CLP and Dicer.

  • The 5‐lipoxygenase pathway is part of the innate immune system.

  • 5‐LOX products are involved in inflammation, allergic reactions, development of cardiovascular disease as well as certain types of cancer.

Keywords: 5‐lipoxygenase; leukotrienes; lipoxins; 5‐HETE; arachidonic acid; C2‐like domain; nonhaem iron

Figure 1.

Conversion of AA to LTs and 5‐HETE.

Figure 2.

(a) Model of human wildtype 5‐LOX derived from the crystal structure of stable 5‐LOX (PDB: 3o8y). Grey, C2‐like domain; green, catalytic domain; orange, ATP‐binding sites; red, active site iron; dark blue, Ser phosphorylation sites; light blue, Tyr phosphorylation sites; purple, Ca2+ binding site. (b) Model of 5‐LOX dimer; orange, ATP‐binding sites. (c) Model structure of the CLP‐5‐LOX complex. Generated from a model structure of 5‐LOX and a structure of CLP (PDB: 1WNJ), as described in Esser et al. (). Grey, 5‐LOX C2‐like β‐sandwich; Blue, 5‐LOX catalytic domain. Trp residues 13, 75 and 102 are in orange. The CLP backbone is in purple, with Lys131 indicated by green spheres.

Figure 3.

Ca2+‐induced formation of 5‐H(P)ETE and LTA4 by 5‐LOX in presence of scaffold factors CLP (stoichiometry 1:1) and/or phosphatidylcholine (PC, 25 µg ml−1).

Figure 4.

Regulation of cellular 5‐LOX activity. 5‐LOX resides as soluble protein in the nucleoplasm or the cytsol, depending on the cell type and/or the phosphorylation status at Ser271 or Ser523. Upon cell stimulation soluble 5‐LOX binds Ca2+ and may become phosphorylated, and then translocates to the nuclear envelope where it binds to the outer or inner nuclear membrane via Ca2+ close to membrane‐integrated FLAP. AA liberated by cPLA2 is transferred via FLAP to 5‐LOX producing LTA4 that is converted by LTC4S (cytosolic side) or LTA4H (intranuclear) to LTC4 or LTB4, respectively.

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Further Reading

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Werz, Oliver, Rådmark, Olof, and Steinhilber, Dieter(Oct 2014) Recent Advances on 5‐Lipoxygenase Biochemistry. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024630]