Characterization of the Orphan Cytochrome P450 CYP135B1 from : Involvement in Metabolism but Not in the Antibacterial Activity of the Antitubercular Drug SQ109.

Fiche publication

Date publication

avril 2025

Journal

ACS infectious diseases

Auteurs

Membres identifiés du Cancéropôle Est :
Dr POCH Olivier

Tous les auteurs :
Sadowski E, Pietrancosta N, Veyron-Churlet R, Boucher JL, Pionneau C, Clodic G, Matheron L, Poch O, Mayer C, Sachon E, Aubry A

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/40176299

Résumé

The rise of multidrug-resistant tuberculosis (TB) has increased the need for new antitubercular (anti-TB) drugs and the identification of novel drug targets. One promising target is () cytochrome P450 enzymes (P450s). This study focuses on the characterization of CYP135B1, a prevalent P450. Using a combination of microbiology, genomics, bioinformatics, docking, spectroscopy, and mass spectrometry, researchers successfully expressed, purified, and characterized CYP135B1. A 3D model was built with AlphaFold 3. The enzyme displayed typical features of P450 proteins and showed strong binding to imidazole derivatives. Notably, CYP135B1 metabolized the anti-TB drug SQ109 by inserting oxygen into its geranyl moiety in a manner distinct from CYP124A1. However, genetic studies using a ΔCYP135B1 mutant strain revealed that CYP135B1 is not required for SQ109's antibacterial activity, as its deletion did not affect drug efficacy despite CYP135B1 metabolizes SQ109.