title: MmPPOX inhibits Mycobacterium tuberculosis lipolytic enzymes belonging to the hormone-sensitive lipase family and alters mycobacterial growth.
abstract: Lipid metabolism plays an important role during the lifetime of Mycobacterium tuberculosis, the causative agent of tuberculosis. Although M. tuberculosis possesses numerous lipolytic enzymes, very few have been characterized yet at a biochemical/pharmacological level. This study was devoted to the M. tuberculosis lipolytic enzymes belonging to the Hormone-Sensitive Lipase (HSL) family, which encompasses twelve serine hydrolases closely related to the human HSL. Among them, nine were expressed, purified and biochemically characterized using a broad range of substrates. In vitro enzymatic inhibition studies using the recombinant HSL proteins, combined with mass spectrometry analyses, revealed the potent inhibitory activity of an oxadiazolone compound, named MmPPOX. In addition, we provide evidence that MmPPOX alters mycobacterial growth. Overall, these findings suggest that the M. tuberculosis HSL family displays important metabolic functions, thus opening the way to further investigations linking the involvement of these enzymes in mycobacterial growth.
authors.affiliation: CNRS - Aix-Marseille Université - Enzymologie Interfaciale et Physiologie de la Lipolyse - UMR 7282, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Delorme
authors.forename: Sadia V
authors.initials: SV
authors.lastname: Diomandé
authors.forename: Luc
authors.initials: L
authors.lastname: Dedieu
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Cavalier
authors.forename: Frédéric
authors.initials: F
authors.lastname: Carrière
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Julien
authors.initials: J
authors.lastname: Leclaire
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fotiadu
authors.forename: Stéphane
authors.initials: S
authors.lastname: Canaan
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007700:Kinetics; D007783:Lactones / Q000494:pharmacology; D008970:Molecular Weight; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D000077403:Orlistat; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000737:chemistry
chemical_list: C578249:5-methoxy-N-3-(meta-phenoxyphenyl)-1,3,4-oxadiazol-2(3H)-one; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007783:Lactones; D010069:Oxadiazoles; D011994:Recombinant Proteins; D000077403:Orlistat; D002787:Sterol Esterase