leukotriene D4 biosynthetic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways resulting in the formation of leukotriene D4. [GOC:TermGenie, GOC:yaf, UniPathway:UPA00880]

Leukotriene D4 (LTD4) biosynthesis is a crucial process in the inflammatory response, particularly in allergic reactions and asthma. It involves a series of enzymatic reactions that convert arachidonic acid, a fatty acid found in cell membranes, into LTD4.

1. **Arachidonic Acid Release:** The process begins with the release of arachidonic acid from membrane phospholipids. This release is triggered by various stimuli, including allergens, inflammatory mediators, and physical injury. Phospholipase A2 (PLA2) is the enzyme responsible for hydrolyzing phospholipids and liberating arachidonic acid.

2. **5-Lipoxygenase (5-LO) Pathway:** Arachidonic acid is then acted upon by 5-lipoxygenase (5-LO), an enzyme that catalyzes the formation of 5-hydroperoxyeicosatetraenoic acid (5-HPETE). This reaction occurs in the nucleus or cytoplasm of cells, depending on the cell type.

3. **Leukotriene A4 (LTA4) Synthesis:** 5-HPETE is further processed by leukotriene A4 synthase (LTA4S) to produce leukotriene A4 (LTA4). LTA4 is a highly unstable epoxide intermediate.

4. **Leukotriene C4 (LTC4) Formation:** LTA4 is then conjugated with glutathione, a tripeptide, by the enzyme LTC4 synthase (LTC4S) to generate leukotriene C4 (LTC4). This conjugation reaction occurs in the cytoplasm.

5. **Leukotriene D4 (LTD4) Formation:** LTC4 is subsequently hydrolyzed by gamma-glutamyltransferase, an enzyme found on the cell surface, to produce leukotriene D4 (LTD4). LTD4 is a potent bronchoconstrictor and is also involved in vascular permeability and mucus secretion.

6. **Leukotriene E4 (LTE4) Formation:** LTD4 is further metabolized by a dipeptidase, yielding leukotriene E4 (LTE4). LTE4 is a less potent but longer-lasting mediator compared to LTD4.

7. **Biological Effects:** The final products of this pathway, LTD4 and LTE4, exert their effects by binding to cysteinyl leukotriene receptors (CysLT1 and CysLT2) on target cells. These receptors are expressed on various cells, including smooth muscle cells, mast cells, and eosinophils. The activation of CysLT receptors leads to a cascade of signaling events that result in bronchoconstriction, vascular permeability, mucus secretion, and inflammation.

The leukotriene D4 biosynthetic process plays a crucial role in the pathogenesis of allergic asthma. It is also implicated in other inflammatory conditions, such as rheumatoid arthritis and inflammatory bowel disease. Therefore, inhibitors of this pathway, such as montelukast and zafirlukast, are effective therapeutic agents for the treatment of asthma and other allergic diseases.'
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