leukotriene A4 metabolic process

Definition

Target type: biologicalprocess

The chemical reactions and pathways involving leukotriene A4. [GOC:TermGenie, GOC:yaf]

Leukotriene A4 (LTA4) metabolic process is a crucial step in the biosynthesis of leukotrienes, a class of potent lipid mediators involved in inflammation, allergy, and immune responses. LTA4 is a highly reactive epoxide intermediate generated from arachidonic acid by the enzyme 5-lipoxygenase. The metabolic process of LTA4 involves its conversion to various biologically active leukotrienes, including LTB4, LTC4, LTD4, and LTE4, by different enzymatic pathways.

**Step 1: Formation of LTA4:**

- Arachidonic acid, a polyunsaturated fatty acid, is released from membrane phospholipids by phospholipase A2.
- 5-lipoxygenase (5-LOX) catalyzes the oxygenation of arachidonic acid at the 5-position, forming 5-hydroperoxyeicosatetraenoic acid (5-HPETE).
- 5-HPETE is then dehydrated by 5-LOX to yield LTA4, a highly reactive epoxide.

**Step 2: Conversion of LTA4 to other leukotrienes:**

- **LTB4 synthesis:** LTA4 hydrolase (LTA4H) catalyzes the hydrolysis of LTA4, producing LTB4, a potent chemoattractant for neutrophils and other inflammatory cells.

- **LTC4, LTD4, and LTE4 synthesis:** LTA4 is conjugated with glutathione by LTC4 synthase, yielding LTC4. LTC4 is then converted to LTD4 by removal of glutamic acid, and further metabolized to LTE4 by removal of glycine. LTC4, LTD4, and LTE4 are collectively known as the cysteinyl leukotrienes and are potent bronchoconstrictors, vasoconstrictors, and mucus secretagogues.

**Regulation of LTA4 metabolism:**

- The activity of 5-LOX, LTA4H, and LTC4 synthase is tightly regulated by various factors, including intracellular calcium levels, phosphorylation, and interaction with other proteins.
- The availability of arachidonic acid, the substrate for 5-LOX, is also crucial in regulating LTA4 metabolism.

**Biological significance:**

- LTA4 metabolism plays a critical role in various physiological and pathological processes, including:

- Inflammation: Leukotrienes contribute to the inflammatory response by mediating chemotaxis, vascular permeability, and leukocyte activation.
- Allergy: Cysteinyl leukotrienes are key mediators of allergic reactions, causing bronchoconstriction, airway hyperresponsiveness, and mucus production.
- Asthma: Leukotrienes contribute to the pathogenesis of asthma, leading to airway inflammation, bronchospasm, and mucus hypersecretion.
- Immune response: Leukotrienes influence the immune response by modulating leukocyte migration and cytokine production.
- Cardiovascular disease: Leukotrienes have been implicated in the development of cardiovascular disease, including atherosclerosis and hypertension.

**Clinical implications:**

- Inhibition of LTA4 metabolism is a therapeutic target for the treatment of inflammatory and allergic disorders, such as asthma, rheumatoid arthritis, and inflammatory bowel disease.
- Several drugs that inhibit LTA4 metabolism have been developed, including leukotriene inhibitors (e.g., montelukast, zafirlukast) and 5-LOX inhibitors (e.g., zileuton).
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Proteins (2)

Compounds (41)