Post-translational modifications of CYP4f11 by 4-hydroxynonenal: ω-hydroxylation impairment and potential role in immunosuppression.

Malaria is a life-threatening parasitic infection caused by Plasmodium parasites, known for triggering immune dysfunction and dysregulation. A hallmark of malaria pathogenesis is oxidative stress: the generating of bioactive lipid peroxidation products such as 4 hydroxynonenal (4-HNE) and accumulation of hydroxyeicosatetraenoic acids (HETEs) were described. Post-translational modification of CYP4F11 by 4-HNE (lipoxidation protein modification) is hypothesized to impair its enzymatic ω-hydroxylation activity, particularly towards 15-HETE, leading to its accumulation and sustained monocyte dysfunction. This process may play a crucial role in immunosuppression during malaria. Experimental analysis, including a combined immunochemical and mass-spectrometric approach, identified six distinct 4-HNE-modified residues in CYP4F11, with C260 and H261 situated in its substrate recognition site. Functional studies revealed that unmodified CYP4F11 binds substrates such as palmitic acid, arachidonic acid, 12-HETE, and 15-HETE with specific dissociation constants, but its conjugation with 4-HNE (in pathophysiological micromolar concentrations) completely inhibits substrate binding and enzymatic activity. Lipid reconstitution systems improved the enzymatic characteristics of unmodified CYP4F11 but failed to restore functionality following 4-HNE induced damage. In conclusion, under malaria conditions, lipid peroxidation-driven modifications of CYP4F11 compromise its role in metabolizing four tested substrates. The accumulation of non metabolized immunosuppressive lipid molecules could disrupt immune signalling pathways and monocyte functionality, contributing to cellular immune suppression and the broader immune imbalance observed in malaria. Notably, these findings could also extend to other conditions characterized by high lipid peroxidation, where similar mechanisms may further exacerbate immune dysregulation.