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.
Highlights
According to the World Health Organization (2011; http:// www.who.int/tb/en/), tuberculosis remains one of the most threatening and deadly disease in the world, with 8.8 million new infections and 1.5 million deaths in 2010
One gene was found to be homologous to a Candida parapsilosis lipase, one to the human bile salt-dependent lipase (BSSL), 12 to the hHSL [16,17,19,20], 7 to the Fusarium solani cutinase (Fs cutinase) [39,40,41,42,43], 4 to monoacylglycerol lipases [44,45] and 4 to phospholipases C (PLC) [30]
We reasoned that the availability of MmPPOX, a known hHSL specific inhibitor [25], may provide new insight regarding the role of the Lip-Hormone-Sensitive Lipase (HSL) family in M. tuberculosis and M. bovis BCG
Summary
According to the World Health Organization (2011; http:// www.who.int/tb/en/), tuberculosis remains one of the most threatening and deadly disease in the world, with 8.8 million new infections and 1.5 million deaths in 2010. It has been shown that M. tuberculosis is able to store triacylglycerols (TAG) as intracellular lipid inclusions (ILI), in vivo, during the infection process [2,3,4,5] and in vitro, under stress conditions [6,7]. Lipolytic enzymes are thought to play critical roles during the intracellular lifetime of M. tuberculosis by participating in the entry into a non-replicating dormant state within host granulomas and/or in dormancy escape, leading to reactivation of the disease
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