5-lipoxygenase and related leukotriene synthesis enzymes (5-LOX pathway enzymes)

5-lipoxygenase (5-LOX) and its associated synthesis enzymes, including 5-lipoxygenase-activating protein (FLAP), leukotriene A4 hydrolase (LTA4H), and leukotriene C4 synthase (LTC4S), constitute the primary metabolic pathway for the production of leukotrienes (Wikipedia, 2024; Karger, 2024). These lipid mediators are central to the inflammatory response, with LTB4 acting as a potent chemoattractant for neutrophils and cysteinyl leukotrienes (LTC4, LTD4, and LTE4) inducing bronchoconstriction, mucus secretion, and vascular permeability (Karger, 2024; ClinPGx, 2024). The pathway is initiated when FLAP presents arachidonic acid to 5-LOX, which converts it into the unstable intermediate LTA4 (NeupsyKey, 2019; MDPI, 2020). Depending on the cell type, LTA4 is then hydrolyzed by LTA4H to form LTB4 or conjugated with glutathione by LTC4S to form cysteinyl leukotrienes (ACS, 2019; ResearchGate, 2024). Dysregulation of the 5-LOX pathway is implicated in a variety of chronic inflammatory diseases, most notably asthma and allergic rhinitis, but also chronic obstructive pulmonary disease (COPD), cardiovascular diseases, and certain cancers (Wikipedia, 2024; Maayanlab, 2024; TandfOnline, 2021). Pharmacological targeting of these enzymes aims to reduce the burden of pro-inflammatory leukotrienes (Probiologists, 2024; NIH, 2024). Zileuton, a 5-LOX inhibitor, is the only enzyme inhibitor in this pathway currently approved for clinical use in asthma, while several inhibitors of FLAP and LTA4H are in various stages of clinical development for conditions like cystic fibrosis and cardiovascular disease (Wikipedia, 2024; NeupsyKey, 2019; TandfOnline, 2021).

Other names

5-lipoxygenase pathwayLeukotriene biosynthesis enzymesALOX5 pathway enzymes5-LO pathway

Inhibition of the enzymatic activity of 5-lipoxygenase (5-LOX), leukotriene A4 hydrolase (LTA4H), or leukotriene C4 synthase (LTC4S), or the inhibition of the 5-lipoxygenase-activating protein (FLAP), thereby preventing the biosynthesis of pro-inflammatory leukotrienes (LTB4 and cysteinyl leukotrienes) from arachidonic acid (NIH, 2024; ACS, 2019).