Institute of Molecular Biosciences, University of Graz, Humboldtstraße 50/3, 8010, Graz, Austria.
BioTechMed-Graz, Mozartgasse 12/II, 8010, Graz, Austria.
Sci Rep. 2018 Jun 12;8(1):8948. doi: 10.1038/s41598-018-27051-7.
Monoacylglycerol lipases (MGLs) are enzymes that hydrolyze monoacylglycerol into a free fatty acid and glycerol. Fatty acids can be used for triacylglycerol synthesis, as energy source, as building blocks for energy storage, and as precursor for membrane phospholipids. In Mycobacterium tuberculosis, fatty acids also serve as precursor for polyketide lipids like mycolic acids, major components of the cellular envelope associated to resistance for drug. We present the crystal structure of the MGL Rv0183 from Mycobacterium tuberculosis (mtbMGL) in open conformation. The structure reveals remarkable similarities with MGL from humans (hMGL) in both, the cap region and the α/β core. Nevertheless, mtbMGL could not be inhibited with JZL-184, a known inhibitor of hMGL. Docking studies provide an explanation why the activity of mtbMGL was not affected by the inhibitor. Our findings suggest that specific inhibition of mtbMGL from Mycobacterium tuberculosis, one of the oldest recognized pathogens, is possible without influencing hMGL.
单酰甘油脂肪酶（MGL）是能够将单酰甘油水解为游离脂肪酸和甘油的酶。脂肪酸可用于三酰甘油合成、作为能量来源、作为储能的构建块以及作为膜磷脂的前体。在结核分枝杆菌中，脂肪酸也是聚酮脂质如分枝菌酸的前体，分枝菌酸是与耐药性相关的细胞包膜的主要成分。我们展示了来自结核分枝杆菌（mtbMGL）的 MGL Rv0183 的开放构象的晶体结构。该结构显示与来自人类的 MGL（hMGL）在帽区域和α/β核心中都具有显著的相似性。然而，mtbMGL 不能被 JZL-184 抑制，JZL-184 是 hMGL 的一种已知抑制剂。对接研究提供了为什么 mtbMGL 的活性不受抑制剂影响的解释。我们的发现表明，对最古老的病原体之一结核分枝杆菌的 mtbMGL 进行特异性抑制是可能的，而不会影响 hMGL。
