臺灣博碩士論文加值系統

本研究的目的為建立高靜水壓 (High hydrostatic pressure, HHP) 輔助酵素水解小球藻 (Chlorella sorokiniana) 渣的最適加工條件，以萃取出具有抑制 DPP-IV 活性之胜肽，並探討高壓對蛋白質結構與酵素活性的影響，透過添加乳酸菌粗酵素液以改善水解物的苦味。小球藻渣分別以 Protamex、Protin NY 100 及 Flavourzyme 於 100 MPa 下誘發 10 min 後水解至 24 hr 並命名為 H-PX、H-NY 100 及 H-Fla，其胜肽含量分別為 307.69、383.13、549.52 mg/g，三者皆具有抑制 DPP-IV 之能力，其 IC50 值分別為 5.51、4.37 及 5.73 mg/mL。將 L. paracasei 菌粉添加於 MRS broth 中活化 24 hr 後於 37℃ 下進行培養，當培養至 24 hr 時以達最大菌數為 1.17×109 CFU/mL，接著進行細胞破碎處理，離心後去除沉澱物即可得乳酸菌粗酵素液 (L. paracasei crude enzyme, LPE)。接著將各組別添加 LPE 後於相同條件下水解製成 L-H-PX、L-H-NY 100 及 L-H-Fla，三者對 DPP-IV 的抑制能力皆有所提升，IC50 值依序為 5.44、4.29 及 5.08 mg/mL。將 L-H-PX、L-H-NY 100 及 L-H-Fla 進行體外腸胃道消化試驗以評估水解物的穩定性，結果顯示各組別的抑制能力皆下降，其中 L-PX 對 DPP-IV 的抑制能力最高，其 IC50 值為 7.61 mg/mL，因此在此選擇 Protamex 作為水解酵素。將 L-H-PX 經不同壓力 (100、200 及 300 MPa) 誘發 10 min 後水解至 24 hr 並命名為 L-H100-PX、L-H200-PX 及 L-H300-PX，胜肽含量分別為 286.05、344.81 及 360.33 mg/g，其中 L-H300-PX 顯示出最高的抑制能力，IC50 值為 4.81 mg/mL，顯示示高壓有助於 DPP-IV 抑制胜肽的釋放。將 L-H-PX 於 300 MPa 下分別誘發 10、15 及 20 min 後進行水解 (L-H-T10PX、L-H-T15PX 及 L-H-T20PX)，其中以 L-H-T10PX 的抑制能力最高，因此後續將以 300 MPa/10 min 作為 HHP 誘發條件。
利用 FTIR 分析小球藻渣的蛋白質二級結構，其經高壓 300 MPa 處理 10min 後的 α-helix 含量下降約 6.51 %，而 β-sheet 與 ꞵ-turn 含量則提升約 2.59 與 16.89%，顯示 HHP 可能會導致分子內的氫鍵受到破壞轉而形成分子間氫鍵。在蛋白質表面疏水性 (H0) 的結果中，小球藻渣蛋白的 H0 由原先的 3450，經高壓處理後則提升至 3547，表示 HHP 可使蛋白質結構展開，造成內部的疏水性基團暴露於表面。利用酵素水解動力學分析壓力對 Protamex 反應速率的影響。結果顯示，Protamex 經高壓處理後的 Vmax 值提升約 43.48%，Km 值則下降約 6.90%，代表 HHP 可提升其反應速率並促進酵素與基質間的親和力。
將 L-H-PX 經最適高壓條件處理後分別水解至 0、3、6 及 24 hr，以找出最適水解條件，其中以 L-H-PX6 對 DPP-IV 的抑制能力最高，IC50 值為 4.33 mg/mL，其可溶性蛋白、胜肽及游離胺基酸含量分別為 560.24、256.65 及 20.46 mg/g。L-H-PX6 經腸胃道酵素水解後 (L-H-PX6-G) 的 IC50 值則提升至 6.08 mg/mL，但仍保有抑制 DPP-IV 之活性。
利用膠體過濾層析將 L-H-PX6-G 劃分出 6 個主要波峰 (A-E fraction)，其中 Fraction E 的抑制能力最高，分子量範圍介於 270-320 Da 之間，IER 為 334.58%/mg/mL。將 Fraction E 進一步以 RP-HPLC 純化出 E1、E2 及 E3 波峰，其中 E2 可鑑定出胜肽 Trp-Ala (WA)，經測定後其 IC50 值為 211.83 μM。最後將胜肽 WA 與 DPP-IV 進行分子對接，經電腦軟體計算後兩者的結合能為 -8.5 kcal/mol，顯示 WA 可與 DPP-IV產生良好的結合力，並可形成 5 個氫鍵。在 WA 序列中，Trp1 可與 DPP-IV S2 位點中的 Glu 205、Glu 206 及 Ser 209 形成氫鍵，Ala2 可與 DPP-IV Catalytic triad 中的 His 740 與 Ser 630 形成氫鍵，上述結合位點與常見的 DPP-IV 抑制劑具有相同之處。綜上所述，期許本研究的成果能提升小球藻渣的商業價值，以開發成調節血糖之保健產品。

The purpose of this study was to set up the optimal processing conditions for high hydrostatic pressure-assisted enzyme hydrolysis of Chlorella sorokiniana residue to produce DPP-IV inhibitory peptides, and the effects of HHP on protein structure and enzyme activity was discussed.On the other hand, the bitterness of the hydrolyzate can be improved by adding lactic acid bacteria crude enzyme. C. sorokiniana residue with Protamex, Protin NY 100 and Flavourzyme was induced at 100 MPa for 10 min and then hydrolyzed to 24 hr (H-PX, H-NY 100 and H-Fla). The peptide contents of H-PX, H-NY 100 and H-Fla were 307.69, 383.13 and 549.52 mg/g, the IC50 values of DPP-IV inhibition were 5.51, 4.37 and 5.73 mg/mL respectively. L. paracasei powder was added to MRS broth for activation for 24 hr and then culture at 37°C, until cultured for 24 hours, the maximum cell count is 1.17×109 CFU/mL. The cells were disrupted, and the precipitate was removed after centrifugation to obtain the L. paracasei crude enzyme (LPE). LPE was added to each group and hydrolyzed under the same conditions (L-H-PX, L-H-NY 100 and L-H-Fla). The results showed that the DPP-IV inhibitory activity of L-H-PX, L-H-NY 100 and L-H-Fla were all improved, with IC50 values of 5.44, 4.29, and 5.08 mg/mL. L-H-PX, L-H-NY 100, and L-H-Fla were subjected to simulated gastrointestinal digestion (SGID) to evaluate the stability of the hydrolyzate. The results showed that the DPP-IV inhibitory ability of each group decreased, among which L-H-PX had the highest inhibitory ability, its IC50 value is 7.61 mg/mL. Therefore, Protamex was selected as the hydrolase. L-H-PX was hydrolyzed after being induced under different pressures (100, 200, 300 MPa) for 10 min. The peptide contents of L-H100-PX, L-H200-PX, and L-H300-PX were 286.05, 344.81 and 360.33 mg/g respectively. L-H300-PX showed the highest DPP-IV inhibitory ability with an IC50 value of 4.81 mg/mL, indicating that HPP promoted the release of DPP-IV inhibitory peptides. L-H-PX was hydrolyzed after being induced at 300 MPa for 10, 15, and 20 min respectively (L-H-T10PX、L-H-T15PX 及 L-H-T20PX). Among them, L-H-T10PX had the highest inhibitory ability, and therefore 300 MPa/10 min was used as the HHP induction factor.
FTIR was used to analyze the protein secondary structure of chlorella residue, the α-helix content after HPP treatment (300 MPa,10 min) decreased by approximately 6.51%, while the β-sheet and ꞵ-turn contents increased by approximately 2.59 and 16.89%. The above result shows that HHP can result in intramolecular hydrogen bonds being broken and intermolecular hydrogen bonds being formed instead. In the results of surface hydrophobicity (H0), the H0 of chlorella residue increased from 3450 to 3547 after high-pressure processing, indicating that HHP can unfold the protein structure, causing internal hydrophobic groups to be exposed to the surface. Enzyme kinetics was used to analyze the effect of pressure on the reaction rate of Protamex. The results showed that the Vmax value of Protamex increased by approximately 43.48% and the Km value decreased by approximately 6.90% after high-pressure processing, which shows that HHP can increase the reaction rate of Protamex and promote the affinity of the enzyme for substrate.
L-H-PX was hydrolyzed to 0, 3, 6, and 24 hr after being induced under optimal HPP conditions. Among them, L-H-PX6 had the highest DPP-IV inhibitory ability with an IC50 value of 4.33 mg/mL, its soluble protein, peptide, and free amino acid contents were 560.24, 256.65, and 20.46 mg/g respectively. The DPP-IV inhibitory activity of L-H-PX6 was retained even though its IC50 increased from 4.33 to 6.08 mg/mL (L-H-PX6-G) by SGID.
Using gel filtration chromatography, L-H-PX6-G was fractioned into six fractions (Fraction A to E ). The molecular weight range of Fraction E was between 270-320 Da and the highest IER on DPP-IV was 334.58%/mg/mL. Further, the Fraction E was purified by RP-HPLC to obtain E1, E2, and E3 peaks. Peptide Trp-Ala (WA) was identified from E2, and its IC50 value was 211.83 μM. Finally, the molecular docking result shows the binding energy of peptide WA and DPP-IV was -8.5 kcal/mol, which can form 5 hydrogen bonds. The result suggested that the peptides could spontaneously bind to DPP-IV. Trp1 of WA was able to form hydrogen bonds with Glu 205, Glu 206, and Ser 209 in the S2 site, and Ala2 was able to form hydrogen bonds with His 740 and Ser 630 in the Catalytic triad. The above binding sites have similarities with common DPP-IV inhibitors. In summary, it is expected that the results of this study can increase the commercial value of chlorella residue and develop it into health supplements to ameliorate type 2 diabetes mellitus.

目錄
摘要 I
Abstract III
目錄 V
圖目錄 IX
表目錄 X
附圖目錄 XI
附表目錄 XII
水解製程縮寫對照表 XIII
壹、前言 1
貳、文獻回顧 3
一、糖尿病 (Diabetes mellitus) 3
1.1 全球概況 3
1.2 糖尿病定義 3
1.3 糖尿病類型 3
1.4 糖尿病治療藥物與副作用 4
二、二肽基肽酶-IV (Dipeptidyl Peptidase-IV, DPP-IV, EC 3.4.14.5) 5
2.1 DPP-IV 特性 5
2.2 調控血糖機制 6
2.3 DPP-IV 抑制劑 6
2.4 食品來源抑制劑 7
三、蛋白質水解 7
3.1 蛋白質水解目的 7
3.2 蛋白質水解方法 7
3.3 酵素水解動力學 9
四、高靜水壓加工技術 9
4.1 HHP 原理 9
4.2 HHP 應用 9
4.3 HHP 輔助酵素水解 10
五、乳酸菌發酵 12
5.1 發酵簡介 12
5.2 乳酸菌 12
5.3 乳酸發酵目的 12
六、小球藻 (Chlorella sorokiniana) 14
6.1 小球藻介紹 14
6.2 小球藻產量與廢棄物 14
6.3 生理活性 14
七、分子對接 (Molecular Docking) 15
7.1 介紹 15
7.2 胜肽與 DPP-IV 之分子對接預測 15
參、實驗架構 17
肆、材料方法 18
一、實驗材料 18
1.1 小球藻渣 (Chlorella sorokiniana) 18
1.2 乳酸菌粉 18
1.3 商業酵素 18
1.4 藥品試劑 18
1.5 電腦軟體 18
1.6 儀器設備 18
二、實驗方法 19
2.1 小球藻渣之一般成分分析 19
2.2 乳酸菌發酵製程 21
2.3 HHP 輔助酵素水解發酵小球藻渣之水解物的製備 22
2.4 pH值測定 23
2.5 可溶性固形物含量測定 24
2.6 利用率 24
2.7 凍乾率 25
2.8 可溶性蛋白質含量測定 25
2.9 胜肽含量之測定 25
2.10 α-胺基酸含量之測定 25
2.11 小球藻渣水解率之測定 26
2.12 蛋白質表面疏水性測定 26
2.13 傅立葉轉換紅外線光譜測量 27
2.14 酵素水解動力學 27
2.15 水解物對 DPP-IV 抑制能力之測定 28
2.16 水解物對 DPP-IV 之 IC50 值測定 29
2.17 模擬腸胃道消化試驗 29
2.18 抑制 DPP-IV 之胜肽序列的純化 29
2.19 抑制 DPP-IV 之胜肽序列的鑑定 30
2.20 分子對接模擬試驗 30
2.21 官能品評 31
2.22 統計分析 31
伍、結果討論 32
一、小球藻渣之一般成分分析 32
二、最適乳酸菌培養時間 32
三、酵素種類之篩選 32
3.1 不同酵素種類經高壓處理後對胜肽含量與 DPP-IV 抑制能力之影響 32
3.2 乳酸菌粗酵素液對胜肽含量與 DPP-IV 抑制能力之影響 33
3.3 腸胃道消化對水解物的胜肽含量與 DPP-IV 抑制能力之影響 33
四、最適高壓條件之篩選 34
4.1 不同高壓壓力對水解物的胜肽含量與 DPP-IV 抑制能力之影響 34
4.2 不同高壓時間對水解物的胜肽含量與 DPP-IV 抑制能力之影響 34
五、最適高壓條件對蛋白質結構之影響 35
5.1 FTIR 分析結果 35
5.2 蛋白質表面疏水性 36
六、酵素水解動力學 36
七、最適常壓水解時間之篩選 37
7.1 不同常壓時間對水解物的胜肽含量與 DPP-IV 抑制能力之影響 37
7.2 不同常壓時間之水解物的水解率與化學組成 37
八、官能品評 38
九、腸胃道消化試驗 39
十、水解物中活性胜肽的純化與鑑定 40
10.1 膠體過濾層析之劃分物 40
10.2 逆相高效液相層析之分離物 40
10.3 ESI/MS/MS 鑑定胜肽序列 41
10.4 胜肽對 DPP-IV 的抑制能力 42
十一、分子對接 42
陸、結論 45
柒、參考文獻 46
圖目錄
圖一、Protamex 水解小球藻渣之酵素動力學圖 63
圖二、Protamex 水解小球藻渣之雙倒數圖 64
圖三、L-H-PX6-G 之膠體過濾層析圖譜 65
圖四、L-H-PX6-G 之 Fraction E 的逆相高效液相層析圖譜 66
圖五、L-H-PX6-G 之 Fraction E 的逆相高效液相層析圖譜 67
圖六、Fraction E 之 E1 逆相高效液相層析單一波峰圖譜 68
圖七、Fraction E 之 E2 逆相高效液相層析單一波峰圖譜 69
圖八、Fraction E 之 E3 逆相高效液相層析單一波峰圖譜 70
圖九、波峰 E2 經 ESI-MS 鑑定之分子量分析結果 71
圖十、波峰 E3 經 ESI-MS 鑑定之分子量分析結果 72
圖十一、波峰 E2 經 ESI-MS/MS 鑑定之胜肽序列結果 73
圖十二、胜肽 WA 與 DPP-IV (3W2T) 的分子對接結果 74

表目錄
表一、小球藻渣之一般成分分析 75
表二、乳酸菌經活化後於不同發酵時間下之菌數、pH值及 OD600 吸光值 76
表三、小球藻渣添加乳酸菌粗酵素液與不同商業酵素於高壓下誘發水解之水解物對胜肽含量與 DPP-IV 抑制活性之影響 77
表四、小球藻渣水解物經模擬腸胃道消化後對胜肽含量與 DPP-IV 抑制活性之影響 78
表五、小球藻渣於不同壓力下誘發水解之水解物對胜肽含量與 DPP-IV 抑制活性的影響 79
表六、小球藻渣於高壓下誘發不同時間後水解之水解物對胜肽含量與 DPP-IV 抑制活性的影響 80
表七、高壓處理對小球藻渣水解物之蛋白質二級結構的影響 81
表八、高壓處理對酵素動力學之 Km 值與 Vmax 的影響 82
表九、小球藻渣於高壓下誘發後水解不同時間對胜肽含量與 DPP-IV 抑制活性的影響 83
表十、小球藻渣於高壓下誘發後水解不同時間對可溶性蛋白、游離胺基酸含量與水解率的影響 84
表十一、不同常壓水解時間與乳酸菌粗酵素液對小球藻渣水解物中鹹味、澀味、苦味、酸味及整體接受度的影響 85
表十二、L-H-PX6 經腸胃道消化酵素水解後對胜肽含量與抑制 DPP-IV 活性的影響 86
表十三、L-H-PX6-G 經膠體過濾層析分離之劃分物的胜肽含量與 DPP-IV 抑制能力 87
表十四、L-H-PX6-G 之劃分物 E 經 RP-HPLC 純化後各波峰 (E1-E3) 的 DPP-IV 抑制能力 88
表十五、E1 之胜肽序列對 DPP-IV 的抑制能力與序列來源 89
表十六、胜肽與 DPP-IV 分子對接的結合位點 90

附圖目錄
附圖一、膠體過濾層析之圖譜基線 91
附圖二、逆相高效液相層析之基線圖譜 92
附圖三、胜肽於質譜儀中產生離子片段的命名方式 93
附圖四、胜肽 WA (Trp-Ala) 的結構式 94

附表目錄
附表一、小球藻渣水解物之利用率、凍乾率、pH 值與 Brix 值 95
附表二、小球藻渣水解物之品評單 96

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