McLean Kirsty J, Dunford Adrian J, Neeli Rajasekhar, Driscoll Max D, Munro Andrew W
Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK.
Arch Biochem Biophys. 2007 Aug 15;464(2):228-40. doi: 10.1016/j.abb.2007.03.026. Epub 2007 Apr 10.
The human pathogen Mycobacterium tuberculosis has made a dramatic resurgence in recent years. Drug resistant and multidrug resistant strains are prevalent, and novel antibiotic strategies are desperately needed to counter Mtb's global spread. The M. tuberculosis genome sequence revealed an unexpectedly high number of cytochrome P450 (P450) enzymes (20), and parallel studies indicated that P450-inhibiting azole drugs had potent anti-mycobacterial activity. This article reviews current knowledge of structure/function of P450s and redox partner systems in M. tuberculosis. Recent research has highlighted potential drug target Mtb P450s and provided evidence for roles of selected P450 isoforms in host lipid and sterol/steroid transformations. Structural analysis of key Mtb P450s has provided fundamental information on the nature of the heme binding site, P450 interactions with azole drugs, the biochemical nature of cytochrome P420, and novel mutational adaptations by which azole binding to P450s may be diminished to facilitate azole resistance.
人类病原体结核分枝杆菌近年来急剧复苏。耐药和多重耐药菌株普遍存在，迫切需要新的抗生素策略来对抗结核分枝杆菌在全球的传播。结核分枝杆菌基因组序列显示细胞色素P450（P450）酶的数量出乎意料地多（20种），同时的研究表明，抑制P450的唑类药物具有强大的抗分枝杆菌活性。本文综述了结核分枝杆菌中P450s和氧化还原伴侣系统的结构/功能的现有知识。最近的研究突出了潜在的药物靶点——结核分枝杆菌P450s，并为选定的P450同工型在宿主脂质和甾醇/类固醇转化中的作用提供了证据。对关键结核分枝杆菌P450s的结构分析提供了关于血红素结合位点的性质、P450与唑类药物的相互作用、细胞色素P420的生化性质以及唑类与P450s结合可能减少以促进唑类耐药性的新突变适应的基本信息。
