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標題: Simultaneous Qualitative and Quantitative Analysis of Cyclic Peptides by CID and ETD Based MS/MS Fragmentation
作者: 阮馨平
Sin-Ping Ruan
關鍵字: 液相層析;質譜分析;環狀胜肽;電子轉儀裂解;LC-MS/MS;Cyclic-peptide;ETD
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The cyclic peptide is one kind of cyclic compounds which combine of the protein and non-protein amino acids, and the carboxyl function at the C-terminus of a peptide forms a peptide bond with the N-terminal amine group a cyclic peptide is formed. A wide variety of cyclic peptides, and all has different biological functions, such as antibodies, anti-bacterial, anti-cancer, anti-immune substances, toxic substances, ion transfer regulators or protein binding inhibitor. The application of the cyclic peptide is quite diverse, for example: animal feed additive, biopesticide, surfactants, cosmetic or human drug. In the past few years, because the overuse of antibiotics, the cyclic peptides from microorganism are gradually attracted the attention of scholars. The research strategy of this experiment is based on mass analysis, using liquid chromatography tandem mass spectrometry (LC-MS/MS) combine with selected reaction monitoring (SRM) to quantitative of five cyclic peptides antibiotics (polymyxin b, colistin a, colistin b, surfactin, iturin a) in a variety of matrices (bacterial, liver and milk), and combine with electron-transfer coupled with collision-induced dissociation (ET/CID) to sequence cyclic peptides, trying to join with metal chloride solution by sheath liquid, that expect to enhance the number of electric charge for cyclic peptides in the electrospray ionization method, and observe whether increases the sequence coverage of ETD, to establishment of a cyclic peptide containing such compounds ET/CID and SRM analysis platform.

環狀胜肽 (cyclic peptide) 是一種較線性多肽更為穩定且具有生理功能和醫藥價值的環狀多肽,由蛋白質或非蛋白質胺基酸藉由酯鍵、胜肽鍵、雙硫鍵所形成之環狀化合物,其廣泛分布、種類繁多且具不同功用,在鎮靜、抗菌、抗腫瘤、免疫抑制、抗酵素水解、抗化學降解、離子載體系統或蛋白質鍵結抑制物等方面展現出豐富多樣的生物活性。近年來,因化學性抗菌藥劑的長期濫用,使微生物來源的環狀胜肽變成潛在抗生素理想替代品之一,成為近期研究趨勢。目前,環狀胜肽的應用漸趨多樣化,如使用於畜牧業作為動物的飼料添加物、農業上的天然農藥、天然界面活性劑,甚至運用在高級化妝品、人類的醫學用藥等。於此以質譜分析技術為基礎,利用液相層析串聯式質譜儀 (liquid chromatography tandem mass spectrometry, LC-MS/MS) 搭配新穎裂解技術電子轉移碰撞引致裂解 (ET/CID) 達到良好定性結果,並結合選擇離子反應偵測模式 (selected reaction monitoring, SRM) 針對環狀胜肽作定量分析,在 ET/CID 定性方面,本身帶有單價數之環狀胜肽母離子,藉由鞘流溶液 (sheath liquid ) 方式添加金屬離子來提升其環狀胜肽之電荷數,提高對電子式裂解之分析效率。在 SRM 定量方面,偵測極限 (limit of detection, LOD) 在 S/N ratio > 3 為 0.41 nM ,定量極限 (limit of quantification, LOQ) 在 S/N ratio > 10 為 1.3 nM ,且變異係數 (CV%) 介於 3 ~ 11 % ;利用此分析平台可檢測出菌液中環狀胜肽含量,且線性範圍 r2 > 0.95 ;此外,針對市售牛奶與豬肝組織,皆未檢測出環狀胜肽,其線性範圍 r2 > 0.95。在本研究結果中,證實以鞘流溶液方式添加金屬離子可增加電荷數,應用於 ET/CID 此電子式裂解模式上,增加裂解資訊提高序列涵蓋率 (sequence coverage),使定性結果擁有較高的可信度,並同時進行定量,建立一個可針對含有環狀胜肽這類化合物的 ET/CID 定性與 SRM 定量分析平台。
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