Niu Yang, Ge Fanglan, Yang Yongzhi, Ren Yao, Li Wei, Chen Guiying, Wen Dongmei, Liu Fuhong, Xiong Li
College of Life Sciences, Sichuan Normal University, Chengdu, 610068 People's Republic of China.
3 Biotech. 2019 May;9(5):169. doi: 10.1007/s13205-019-1703-y. Epub 2019 Apr 8.
The metabolism of host cholesterol by is an important factor for both its virulence and pathogenesis. However, the rationale for this cholesterol metabolism has not been fully understood yet. In the present study, we characterized several previously undescribed acyl-CoA synthetases that are involved in the steroid side-chain degradation in , and an analogue of intermediate from steroid degradation, 5'--(lithocholoyl sulfamoyl) adenosine (LCA-AMS), was successfully designed and synthesized to be used as a specific anti-mycobacterial agent. The acyl-CoA synthetases exhibited strong preferences for the length of side chain. FadD19 homologs, including FadD19 (MSMEG_5914), FadD19-2 (MSMEG_2241), and FadD19-4 (MSMEG_3687), are unanimously favorable cholesterol with a C8 alkanoate side chain. FadD17 (MSMEG_5908) and FadD1 (MSMEG_4952) showed high preferences for steroids, containing a C5 alkanoate side chain. FadD8 (MSMEG_1098) exhibited specific activity toward cholestenoate with a C8 alkanoate side chain. An acylsulfamoyl analogue of lithocholate, 5'--(lithocholoyl sulfamoyl) adenosine (LCA-AMS), was designed and synthesized. As expected, the intermediate analogue not only specifically inhibited those steroid-activated acyl-CoA synthetases, but also selectively inhibited the growth of mycobacterial species, including , , and . Overall, our research advanced our understanding of mycobacterial steroid degradation and provided new insights to develop novel mechanism-based anti-mycobacterial agents.
宿主胆固醇的代谢对其毒力和发病机制而言都是一个重要因素。然而，这种胆固醇代谢的基本原理尚未完全明晰。在本研究中，我们鉴定了几种先前未描述的酰基辅酶A合成酶，它们参与了[具体微生物名称未给出]中类固醇侧链的降解过程，并且成功设计并合成了一种类固醇降解中间体的类似物，即5'-（石胆酰氨磺酰基）腺苷（LCA-AMS），用作特异性抗分枝杆菌剂。这些酰基辅酶A合成酶对侧链长度表现出强烈偏好。FadD19同源物，包括FadD19（MSMEG_5914）、FadD19-2（MSMEG_2241）和FadD19-4（MSMEG_3687），一致偏好带有C8链烷酸侧链的胆固醇。FadD17（MSMEG_5908）和FadD1（MSMEG_4952）对含有C5链烷酸侧链的类固醇表现出高度偏好。FadD8（MSMEG_1098）对带有C8链烷酸侧链的胆甾烯酸表现出特异性活性。设计并合成了石胆酸的酰氨磺酰类似物5'-（石胆酰氨磺酰基）腺苷（LCA-AMS）。正如预期的那样，该中间体类似物不仅特异性抑制那些类固醇激活的酰基辅酶A合成酶，还选择性抑制包括[具体微生物名称未给出]、[具体微生物名称未给出]和[具体微生物名称未给出]在内的分枝杆菌属物种的生长。总体而言，我们的研究增进了我们对分枝杆菌类固醇降解的理解，并为开发基于新机制的抗分枝杆菌剂提供了新见解。
