Enzymes in the 5-Lipoxygenase Pathway and Their Role in Disease

The 5-Lipoxygenase (5-LO) pathway of archidonic acid metabolism is characterized by a number of enzymes that drive both pro-inflammatory and anti-inflammatory functions. The goal of programs targeting this pathway is to either block the pro-inflammatory function or promote the anti-inflammatory function, or both. Leukotrienes (LTs) are such a family of pro-inflammatory products. They are broadly divided into two classes: LTB4 and the cysteinyl leukotrienes (cys-LTs) which include LTC4, LTD4, and LTE4. Leukotrienes are synthesized by a specific set of enzymes (see figure below) and act through receptors to elicit a multitude of biological functions.

The following diagram shows enzymes involved in the synthesis of LTA4, LTB4, and the cysteinyl leukotrienes, LTC4, LTD4, and LTE4:

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Different leukotrienes have different functions and produce different biological responses. For example, Leukotriene B4 (LTB4) stimulates neutrophil infiltration resulting in emphysematous lung tissue and is significantly implicated in the progression of COPD (Chronic Obstructive Pulmonary Disease), a condition considered to be a major and growing social health problem. LTB4 can be inhibited by blocking LTA4 Hydrolase, the enzyme responsible for the production of LTB4. More recent evidence has shown that LTA4H is also involved in the breakdown of the pro-inflammatory tripeptide, proline-glycine-proline (PGP). This has particular significance in COPD as PGP is believed to be released/formed from degrading tissue in the diseased lung and is an important factor in the recruitment of inflammatory cells to the lung.

Leukotrienes, both LTB4 and cysteinyl leukotirnes (cys-LTs), have been linked to ocular inflammatory conditions. Levels of leukotrienes have been shown to be elevated in patients with ocular inflammatory disorders and therapies that block the function of certain leukotrienes demonstrate clinical benefit. In experimental models of uveitis, inhibitors of 5-LO have been shown to reduce the clinical signs of the disease and also reduce levels of LTB4 in the aqueous humour. Given treatment options for serious ocular conditions, which may be either expensive or have associated side-effects, 5-LO is an attractive target for new treatments.