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研究生(外文):Nur Maulida Safitri
論文名稱(外文):Screening of Bioactive Peptides with Angiotensin-I Converting Enzyme Inhibition and Antioxidative Activities from Enzymatic Hydrolysates of Spirulina platensis and Chlorella sorokiniana
指導教授(外文):Hsu, Jue-LiangEndang Yuli Herawati
口試委員(外文):Chang, Chi-IWu-Yu Jen
中文關鍵詞:ACE 抑制胜肽抗氧化胜肽半抑制濃度胜肽水解物
外文關鍵詞:ACEI peptideantioxidant peptideIC50Protein hydrolysateChlorella sorokinianaSpirulina platensis
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血管縮素轉化酶(Angiotensin-I Converting Enzyme, ACE)在與調節血壓相關之腎素-血管收縮素-醛固酮系統(Renin-Angiotensin-Aldosterone System, RAAS)及激肽釋放酶-激肽系統(kallikrein- kinin system, KKS)中扮演重要的角色。ACE抑制劑被廣泛應用於降血壓。綠藻(又稱小球藻,Chlorella sorokiniana)和藍藻(又稱螺旋藻,Spirulina platensis)是具有高蛋白質含量(乾重40-70%)的食用微藻,由於其多樣的生物活性,長久以來被用作營養補充品或機能性食品。文獻曾報導藍藻蛋白(S. platensis protein, SPP)可被不同酵素(如:鹼性蛋白酶及胃蛋白酶)水解生成降血壓活性胜肽,但綠藻蛋白(C. sorokiniana protein, CSP)水解物之降血壓胜肽尚未被報導。嗜熱菌蛋白酶(thermolysin)具有廣泛特異性及易生成N端疏水性殘基的特性,極具潛力可生成抑制ACE 之活性胜肽。然而,以嗜熱菌蛋白酶水解SPP及CSP生成具抑制ACE活性胜肽之文獻尚未被報導。本研究以不同酵素對上述二種藻類進行水解,發現以嗜熱菌蛋白酶之藍、綠藻水解物具有最佳之ACE抑制活性,在濃度83.3 µg/mL之抑制活性分別為82.60±0.16%及80.54±0.75%。接著,以逆相層析(reversed-phase high performance liquid chromatography, RP-HPLC)及強陽離子交換層析(strong-cation exchange chromatography, SCX)進行藍、綠藻之嗜熱菌蛋白酶水解物之分群,各分液再進行ACE抑制活性評估,並以液相層析-串聯式質譜分析(LC-MS/MS),分別從CSP及SPP篩選出活性胜肽YR5/ IK15及 IR5 /FY11。其中,IR5半抑制濃度( IC50 = 10.54±1.38 µM)最低。由抑制動力學的結果顯示IR5為非競爭抑制劑,而分子模擬的結果也支持此結果,即IR5與ACE之作用並未落在活性中心。此外,利用類似方法,我們也初步篩選到一些具抗氧化活性之胜肽。本研究結果顯示,藍、綠藻之嗜熱菌蛋白酶水解物存在抑制ACE及抗氧化之活性胜肽,具有防止及治療高血壓之潛力。
Angiotensin-I Converting Enzyme (ACE, EC plays an important role in Renin Angiotensin Aldosterone System (RAAS) and Kallikrein Kinin System (KKS) system of blood pressure regulation. ACE inhibitors (ACEi) are widely used to treat hypertension. Chlorella sorokiniana and Spirulina platensis are edible microalgae with high protein content (40-70% of its dry weight) and have been used as nutraceuticals and functional foods due to its biological activities. Different enzymes have been used for the digestion of S. platensis protein (SPP) containing antihypertensive peptides such as alcalase (Lu et al., 2010) and pepsin (Suetsuna et al., 2001) can be found in the literature, whereas there has no antihypertensive peptide from C. sorokiniana protein (CSP) been reported yet. It has been suggested that thermolysin is the most preferrable due to its broad specificity to generate hydrophobic residues at peptide N-termini. Nevertheless, the use of this enzyme for digesting CSP and SPP peptide has not been elucidated. In this study, thermolysin hydrolysate inhibited 82.60±0.16% and 80.54±0.75% ACE activity at 83.3 µg/mL, which demonstrated potent ACEi activity compared with other enzymes. Subsequently, the thermolysin hydrolysate then was fractionated using two orthogonal bioasssay-guided fractionations using reversed-phase high performance liquid chromatography (RP-HPLC) and strong-cation exchange chromatography (SCX) separation. Peptides YR5 & IK15 from CSP and IR5 & FY11 were characterized and IR5 peptide was further examine its ACE inhibitory activity due to its lowest IC50 (10.54±1.38 µM). This peptide was regarded as non-competitive ACE inhibitor according to inhibition kinetics study. Molecular docking simulation was further conducted to predict the interaction between IR5 and ACE. The result indicates that the preferable interaction is out of ACE active site, which is consistent with the result obtained from inhibition kinetics. Preliminary studies was also conducted to find potential peptide as antioxidant. Our result demonstrate that CSP and SPP are promising material to obtain potential bioactive peptide as ACE inhibitor and antioxidant in the prevention and treatment of hypertension.
中文摘要 ii
1.1 Background 1
1.2 Future Impact 4
2.1 The Renin-Angiotensin—Kallikrein-Kinin and Mitochondrial System 5
2.2 Angiotensin Converting Enzyme 7
2.2.1 Structure of Angiotensin Converting Enzyme 7
2.2.2 ACE substrates 9
2.3 Synthetic ACE inhibitors 10
2.4 Bioactive Peptides 11
2.5 Biological Sources Derived from Microalgae 12
2.6 Methods for Separation of Bioactive Peptide 13
2.6.1 RP-HPLC Method 13
2.6.2 Strong Cation Exchange Chromatography Method 14
2.7 Methods for Identification of Bioactive Peptide 14
2.7.1 LC-MS/MS Method 14
2.7.2 Database Search 15
2.7.3 De Novo Sequencing 15
2.8 Measurements of ACEI Inhibition Mode 16
2.9 Gastrointestinal Enzyme Simulation 16
III. Materials and Methods 18
3.1 Experimental Design 18
3.2 Materials and Chemical Reagents 19
3.3 Instruments 20
3.4 Experimental Protocols 20
3.4.1 Cell Disruption 20
3.4.2 Optimization of Protein Purification 21
3.4.3 SDS PAGE-In Gel Digestion 21
3.4.4 Preparation of enzymatic hydrolysates Chlorella sorokiniana Protein (CSP) and Spirulina platensis Protein (SPP) 22
3.4.5 Desalting 22
3.4.6 Separation of Hydrolysate 23 Fractionation using RP-HPLC 23 Fractionation using Offline SCX 23
3.4.7 ACE and DPPH Inhibitory Studies 23 ACE Inhibitory Assay 23 DPPH Inhibitory Assay 25 IC50 Value Determination 25
3.4.8 Identification of Bioactive Peptides Sequence 25 LC-MS/MS Condition 25 Mascot Search Protein Database 26 De Novo Sequencing 27
3.4.9 Peptide Synthesis 27
3.4.10 Peptide Purification using RP-HPLC 28
3.4.11 MRM Study of Protein Hydrolysates 28
3.4.12 Determination of Stability of Peptides to ACE 29
3.4.13 Determination of the Inhibition Pattern of ACEi Peptide 29
3.4.14 Molecular Docking Study 30
3.4.16 Statistical Analysis 31
4.1 Preparation of enzymatic hydrolysate and its ACE inhibitory activities 32
4.3 Identification of ACE Inhibitory Peptide using LC-MS/MS, Database-Assisted Sequencing and De Novo Sequencing 36
4.4 Synthetic Peptide Identification and Purification by RP-HPLC and LC-MS 40
4.4.1 CSP Peptide Characterization 40
4.5 Confirmation of IC50 value ACE inhibition from synthetic peptide 46
4.5.1 IC50 value of ACEi Peptides derived from CSP 46
4.6 Characterization of Peptides Stability to ACE 47
4.7 Inhibitory Kinetics of ACEI Peptides from Microalgae 48
4.7.1 Kinetics Study of ACEi peptide from CSP 48
4.7.2 Kinetics Study of ACEi peptide from SPP 49
4.8 MRM Quantification of Peptide ILLYR on Thermolysin Hydrolysate of S. platensis 50
4.9 Molecular Modelling of Peptides and ACE 51
4.9.1 YDYNR and ACE 51
4.11 Protein Profiling of CSP and SPP by SDS Page 55
4.12 Antioxidative Properties of CSP and SPP 57
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