Human Orphan Cytochrome P450 2U1 Catalyzes the ω-Hydroxylation of Leukotriene B₄

Cytochrome P450 2U1 (CYP2U1) identified from the human genome remains poorly known since few data are presently available on its physiological function(s) and substrate(s) specificity. CYP2U1 mutations are associated with complicated forms of hereditary spastic paraplegia, alterations of mitochondrial architecture and bioenergetics. In order to better know the biological roles of CYP2U1, we used a bioinformatics approach. The analysis of the data invited us to focus on leukotriene B₄ (LTB₄), an important inflammatory mediator. Here, we show that CYP2U1 efficiently catalyzes the hydroxylation of LTB₄ predominantly on its ω-position. We also report docking experiments of LTB₄ in a 3D model of truncated CYP2U1 that are in agreement with this hydroxylation regioselectivity. The involvement of CYP2U1 in the metabolism of LTB₄ could have strong physiological consequences in cerebral pathologies including ischemic stroke because CYP2U1 is predominantly expressed in the brain.