N-肉豆蔻酰基转移酶家族的进化踪迹分析研究  

Evolutionary trace analysis of N-myristoyltransferase family

作　　者：盛春泉[1] 朱杰[2] 张万年[1] 徐辉[1] 缪震元[1] 姚建忠[1] 张珉[1] 

机构地区：[1]第二军医大学药学院,上海200433 [2]第二军医大学科研部,上海200433

出　　处：《药学学报》2007年第2期157-165,共9页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(30400567).

摘　　要：为了阐明抗真菌药物作用新靶点———N-肉豆蔻酰基转移酶(NMT)活性位点中的关键功能残基分布,指导设计特异性抑制剂,开展了NMT家族的蛋白多元序列联配研究,并构建了蛋白系统进化树。在此基础上,采用进化踪迹分析技术识别得到了NMT活性位点中肉豆蔻酰CoA结合位点、催化反应中心和抑制剂结合位点的重要功能残基。通过对白色念珠菌NMT活性位点中药物结合位点的研究发现,Trp126,Asn175和Thr211是NMT家族的高度保守残基,而且不与已有的抑制剂发生直接的相互作用,因此将是发现新型NMT抑制剂的重要药物结合位点。亚家族特异性残基Pro338,Leu350,Ile352和Ala353可作为已有抑制剂结构优化的重要位点,据此设计的新化合物将有望进一步提高对真菌NMT的选择性。进化踪迹分析结果为进一步阐明NMT结构-功能关系和新型NMT抑制剂类抗真菌药物的设计提供重要信息。TO clarify the important functional residues in the active site of N-myristoyltransferase （NMT） , a novel antifungal drug target, and to guide the design of specific inhibitors, multiple sequence alignments were performed on the NMT family and thus evolutionary trace was constructed. The important functional residues in myristoyl CoA binding site, catalytic center and inhibitor binding site of NMT family were identified by ET analysis. The trace residues were mapped onto the active site of CaNMT. Trp126, Asn175 and Thr211 are highly conserved trace residues and do not interact with current NMT inhibitors, which are potential novel drug binding sites for the novel inhibitor design. Pro338, Leu350, Ile352 and Ala353 are class-specific trace residue inhibitors. The trace residues identifieds, function relationship and also to guide the d which are important for the optimization of current NMT ET analysis are of great importance to study the structureesigu of specific inhibitors.

关 键 词：N-肉豆蔻酰基转移酶 进化踪迹分析 药物结合位点 

分 类 号：R916.693[医药卫生—药学]