Academic Journal
A disease‐associated missense mutation in CYP4F3 affects the metabolism of leukotriene B4 via disruption of electron transfer
| Τίτλος: | A disease‐associated missense mutation in CYP4F3 affects the metabolism of leukotriene B4 via disruption of electron transfer |
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| Συγγραφείς: | Elien Smeets, Shengyun Huang, Xiao Yin Lee, Erika Van Nieuwenhove, Christine Helsen, Florian Handle, Lisa Moris, Sarah El Kharraz, Roy Eerlings, Wout Devlies, Mathijs Willemsen, Leoni Bücken, Teresa Prezzemolo, Stephanie Humblet‐Baron, Arnout Voet, Anne Rochtus, Ann Van Schepdael, Francis deZegher, Frank Claessens |
| Πηγή: | Journal of Cachexia, Sarcopenia and Muscle, Vol 13, Iss 4, Pp 2242-2253 (2022) |
| Στοιχεία εκδότη: | Wiley, 2022. |
| Έτος έκδοσης: | 2022 |
| Συλλογή: | LCC:Diseases of the musculoskeletal system LCC:Human anatomy |
| Θεματικοί όροι: | CYP4F3, LTB4, POR, Cytb5, Exhaustion, Muscle weakness, Diseases of the musculoskeletal system, RC925-935, Human anatomy, QM1-695 |
| Περιγραφή: | Abstract Background Cytochrome P450 4F3 (CYP4F3) is an ω‐hydroxylase that oxidizes leukotriene B4 (LTB4), prostaglandins, and fatty acid epoxides. LTB4 is synthesized by leukocytes and acts as a chemoattractant for neutrophils, making it an essential component of the innate immune system. Recently, involvement of the LTB4 pathway was reported in various immunological disorders such as asthma, arthritis, and inflammatory bowel disease. We report a 26‐year‐old female with a complex immune phenotype, mainly marked by exhaustion, muscle weakness, and inflammation‐related conditions. The molecular cause is unknown, and symptoms have been aggravating over the years. Methods Whole exome sequencing was performed and validated; flow cytometry and enzyme‐linked immunosorbent assay were used to describe patient's phenotype. Function and impact of the mutation were investigated using molecular analysis: co‐immunoprecipitation, western blot, and enzyme‐linked immunosorbent assay. Capillary electrophoresis with ultraviolet detection was used to detect LTB4 and its metabolite and in silico modelling provided structural information. Results We present the first report of a patient with a heterozygous de novo missense mutation c.C1123 > G;p.L375V in CYP4F3 that severely impairs its activity by 50% (P 0.9 for both co‐immunoprecipitation with POR and Cytb5). In silico modelling of CYP4F3 in complex with POR and Cytb5 suggests that the loss of catalytic activity of the mutant CYP4F3 is explained by a disruption of an α‐helix that is crucial for the electron shuffling between the electron carriers and CYP4F3. Interestingly, zileuton still inhibits ex vivo LTB4 production in patient's whole blood to 2% of control (P |
| Τύπος εγγράφου: | article |
| Περιγραφή αρχείου: | electronic resource |
| Γλώσσα: | English |
| ISSN: | 2190-6009 2190-5991 |
| Relation: | https://doaj.org/toc/2190-5991; https://doaj.org/toc/2190-6009 |
| DOI: | 10.1002/jcsm.13022 |
| Σύνδεσμος πρόσβασης: | https://doaj.org/article/7d73d180cc02422d9887d30e1f9063be |
| Αριθμός Καταχώρησης: | edsdoj.7d73d180cc02422d9887d30e1f9063be |
| Βάση Δεδομένων: | Directory of Open Access Journals |
| ISSN: | 21906009 21905991 |
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| DOI: | 10.1002/jcsm.13022 |