生物工程學(xué)報 25 June 2009, 25(6):847～853
高效液相色譜-串聯(lián)質(zhì)譜分析微量格爾德霉素類似物
倪四陽1, 張侃1, 2, 王玉成1, 赫衛(wèi)清1, 王以光1, 賀玖明3, 武臨專1
1 中國醫(yī)學(xué)科學(xué)院/北京協(xié)和醫(yī)學(xué)院醫(yī)藥生物技術(shù)研究所 衛(wèi)生部抗生素生物工程重點實驗室, 北京 100050
2 沈陽藥科大學(xué)制藥工程學(xué)院, 沈陽 110016
3 中國醫(yī)學(xué)科學(xué)院/北京協(xié)和醫(yī)學(xué)院藥物研究所, 北京 100050
摘 要: 安莎類抗生素例如利福霉素和安絲菌素, 通常由一組化學(xué)結(jié)構(gòu)相似的組分組成。格爾德霉素為苯安莎類抗生素,已經(jīng)發(fā)現(xiàn)4個組分,。本研究采用高效液相色譜-串聯(lián)質(zhì)譜方法對格爾德霉素(GDM)制品中的微量組分進(jìn)行了分析, 發(fā)現(xiàn)5個新的和1個已知的GDM類似物。依據(jù)質(zhì)譜數(shù)據(jù),、結(jié)合GDM生物合成機制, 對6個GDM類似物的化學(xué)結(jié)構(gòu)進(jìn)行了推測: 分子式為C29H42N2O10的新化合物3個, 分別為GDM安莎鏈上C2-C3,、C4-C5和C8-C9之間的C-C雙鍵變?yōu)閱捂I并同時單羥基化的GDM衍生物; 分子式為C28H38N2O8的新化合物2個, 其中1個為17(或12, 或4)-去甲氧基格爾德霉素, 另1個為4, 5-雙氫-10, 11-脫水-17-去甲基-17-羥基格爾德霉素; 分子式為C29H42N2O的已知化合物1個, 為4,5-雙氫格爾德霉素,。這些GDM類似物的發(fā)現(xiàn)有助于加深對GDM生物合成的認(rèn)識, 并對通過基因阻斷、組合生物合成技術(shù)獲得GDM衍生物的研究有啟示作用,。
關(guān)鍵詞: 高效液相色譜-串聯(lián)質(zhì)譜, 格爾德霉素, 格爾德霉素類似物, 生物合成
Analysis of geldanamycin analogues in trace amounts by LC-MS/MS
Siyang Ni1, Kan Zhang1, 2, Yucheng Wang1, Weiqing He1, Yiguang Wang1, Jiuming He3,and Linzhuan Wu1
1 Key Laboratory of Biotechnology of Antibiotics, Ministry of Health, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking union Medical College, Beijing 100050, China
2 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110015, China
3 Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking union Medical College, Beijing 100050, China
Abstract: Ansamycins, such as rifamycin and ansamitocin, usually consist of a group of structural similar components. Geldanamycin, a benzenic ansamycin, has been found to consist of four structural similar components. We analyzed the geldanamycin (GDM) preparation from Streptomyces hygroscopicus 17997 by LC-ESI(+)-MS/MS, and discovered five novel and one known GDM analogues in trace amounts. Based on the ESI(+)-MS/MS spectra of these GDM analogues, and the present understanding of GDM biosynthesis, we proposed the possible chemical structures of these GDM analogues. Three novel GDM analogues, all having the same molecular formula of C29H42N2O10, were GDM biosynthetic derivatives with one of the three C-C double bonds between C2-C3, C4-C5 and C8-C9 in GDM changed to mono-hydroxylated C-C single bond. The other two novel GDM analogues, having the same molecular formula of C28H38N2O8, were 17(or 12, or 4)-desmethoxylgeldanamycin and 4,5-dihydro-10,11-dehydrate-17-desmethyl-17-hydroxylgeldanamycin, respectively. The known GDM analogue, having the molecular formula of C29H42N2O99, was 4, 5-dihydrogeldanamycin, an intermediate in GDM biosynthesis. The discovery of novel GDM analogues provided us new insights in understanding the biosynthetic details of GDM, and clues of obtaining GDM derivatives by gene-disruption and combinatorial biosynthesis.
Keywords: LC-MS/MS, geldanamycin, geldanamycin analogues, biosynthesis
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