Target type: biologicalprocess
The chemical reactions and pathways resulting in the breakdown of leukotriene B4, a leukotriene composed of (6Z,8E,10E,14Z)-eicosatetraenoic acid having (5S)- and (12R)-hydroxy substituents. [GOC:yaf, PMID:9799565]
Leukotriene B4 (LTB4) catabolism is a critical process for resolving inflammation and restoring tissue homeostasis. LTB4, a potent lipid mediator produced by leukocytes, orchestrates diverse inflammatory responses, including neutrophil chemotaxis, adhesion, and activation. Its excessive production can contribute to chronic inflammatory diseases.
LTB4 catabolism is primarily mediated by two key enzymes:
- **ω-oxidation:** This process is catalyzed by **cytochrome P450 monooxygenases** (CYP4F enzymes), which introduce a hydroxyl group at the ω-carbon of the LTB4 molecule. This step generates **20-hydroxy-LTB4 (20-OH-LTB4)**, a less potent metabolite.
- **β-oxidation:** 20-OH-LTB4 is then further metabolized by **β-oxidation enzymes** (mainly in peroxisomes) to produce shorter chain fatty acids. This sequential removal of two-carbon units from the carboxyl end of the molecule leads to the formation of inactive metabolites.
**Specific Steps in the Catabolic Pathway:**
1. **Initial Hydroxylation:** LTB4 is oxidized by CYP4F enzymes to form 20-OH-LTB4.
2. **β-Oxidation Cycle:** 20-OH-LTB4 enters the β-oxidation pathway, where it undergoes a series of enzymatic steps. These steps include:
- **Dehydrogenation:** Removal of two hydrogen atoms from the carbon chain, catalyzed by acyl-CoA dehydrogenase.
- **Hydration:** Addition of a water molecule to the unsaturated carbon chain, catalyzed by enoyl-CoA hydratase.
- **Dehydrogenation:** Another removal of hydrogen atoms, catalyzed by hydroxyacyl-CoA dehydrogenase.
- **Thiolysis:** Cleavage of the carbon chain, catalyzed by thiolase.
3. **Formation of Short-Chain Fatty Acids:** These steps are repeated, producing shorter chain fatty acids with each cycle until the molecule is completely degraded.
**Regulation of LTB4 Catabolism:**
The activity of CYP4F enzymes and β-oxidation enzymes can be influenced by various factors, including:
- **Substrate availability:** Increased LTB4 levels stimulate the catabolic process.
- **Hormonal regulation:** Hormones such as glucocorticoids can enhance LTB4 catabolism by upregulating the expression of CYP4F enzymes.
- **Inflammatory stimuli:** Certain inflammatory mediators can modulate the activity of catabolic enzymes.
**Consequences of Impaired Catabolism:**
Reduced LTB4 catabolism can lead to:
- **Persistent inflammation:** Accumulation of LTB4 can exacerbate inflammatory responses, contributing to chronic diseases.
- **Tissue damage:** Excessive LTB4 levels can induce tissue damage and impair repair processes.
**Therapeutic Implications:**
Understanding the mechanisms of LTB4 catabolism has implications for developing novel therapeutic strategies for inflammatory diseases:
- **CYP4F inhibitors:** Inhibition of CYP4F enzymes can increase LTB4 levels, potentially enhancing inflammatory responses.
- **β-oxidation modulators:** Targeting β-oxidation enzymes could modulate LTB4 catabolism and affect inflammation.
**Conclusion:**
LTB4 catabolism is a critical process for resolving inflammation and restoring tissue homeostasis. The enzymatic pathways involved in this process provide potential targets for therapeutic intervention in various inflammatory conditions.'
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Protein | Definition | Taxonomy |
---|---|---|
Cytochrome P450 4F3 | A cytochrome P450 4F3 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q08477] | Homo sapiens (human) |
Cytochrome P450 4A11 | A cytochrome P450 4A11 that is encoded in the genome of human. [PRO:DNx, UniProtKB:Q02928] | Homo sapiens (human) |
Cytochrome P450 4F2 | A cytochrome P450 4F2 that is encoded in the genome of human. [PRO:DNx, UniProtKB:P78329] | Homo sapiens (human) |
Compound | Definition | Classes | Roles |
---|---|---|---|
17-octadecynoic acid | octadec-17-ynoic acid : An acetylenic fatty acid that is octadecanoi acid (stearic acid) which has been doubly dehydrogenated at positions 17 and 18 to give the corresponding alkynoic acid. | acetylenic fatty acid; long-chain fatty acid; monounsaturated fatty acid; terminal acetylenic compound | EC 1.14.14.94 (leukotriene-B4 20-monooxygenase) inhibitor; EC 1.14.15.3 (alkane 1-monooxygenase) inhibitor; P450 inhibitor |
ketoconazole | 1-acetyl-4-(4-{[2-(2,4-dichlorophenyl)-2-(1H-imidazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy}phenyl)piperazine : A dioxolane that is 1,3-dioxolane which is substituted at positions 2, 2, and 4 by imidazol-1-ylmethyl, 2,4-dichlorophenyl, and [para-(4-acetylpiperazin-1-yl)phenoxy]methyl groups, respectively. | dichlorobenzene; dioxolane; ether; imidazoles; N-acylpiperazine; N-arylpiperazine | |
tranylcypromine | (1R,2S)-tranylcypromine : A 2-phenylcyclopropan-1-amine that is the (1R,2S)-enantiomer of tranylcypromine. tranylcypromine : A racemate comprising equal amounts of (1R,2S)- and (1S,2R)-2-phenylcyclopropan-1-amine. An irreversible monoamine oxidase inhibitor that is used as an antidepressant (INN tranylcypromine). Tranylcypromine: A propylamine formed from the cyclization of the side chain of amphetamine. This monoamine oxidase inhibitor is effective in the treatment of major depression, dysthymic disorder, and atypical depression. It also is useful in panic and phobic disorders. (From AMA Drug Evaluations Annual, 1994, p311) | 2-phenylcyclopropan-1-amine | |
proadifen hydrochloride | |||
pirlindole | pirlindole: RN given refers to parent cpd; synonym pyrazidol refers to mono-HCl; structure in Negwer, 5th ed, #2812 | carbazoles | |
17-dihydroexemestane | |||
kaf156 | ganaplacide: antimalarial |