Enzymatic-Catalyzed Mechanisms of Cope Rearrangement of Stig Cyclases: Cation-pi Interactions Stabilizes the Unstable Intermediate

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曾耀弘(Yao Hong Zeng) 查詢紙本館藏

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化學學系

論文名稱

(Enzymatic-Catalyzed Mechanisms of Cope Rearrangement of Stig Cyclases: Cation-pi Interactions Stabilizes the Unstable Intermediate)

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摘要(中)

Stig環化酶: FamC1或 HpiC1酵素可進行催化 3-香葉-3-異氰乙烯基-3H -吲哚轉換為hapalindole型生物鹼。Stig 環化酶催化反應共三步驟: 第一步為香葉基轉移，又稱作Cope 重排反應；第二步與第三步為兩階段環化。其中Cope 重排反應為速率決定步驟，然而Stig環化酶對其催化反應的功能依舊是不清楚。在本研究中，我們研究FamC1 蛋白，先利用分子動力學進行結構平衡，再使用傘狀抽樣結合量子力學/分子動力學的分子動態模擬以及密度泛函理論，研究Cope重排反應的催化機制。我們發現天門冬胺酸214，在酪胺酸89和水分子的輔助下，能啟動質子轉移並進行酸催化反應。而Cope重排反應過程中，會產生陽離子的中間物而與苯丙胺酸88產生陽離子-交互作用，並與酪胺酸產生pi-pi交互作用，影響Cope重排反應路徑、穩定中間物。另外，在酵素的活性中心，我們觀察到在進行Cope重排反應中，酪胺酸101與反應物會有-交互作用。Stig環化酶相關的序列保留與突變實驗結果顯示，上述提到的苯丙胺酸88、酪胺酸89、酪胺酸101、天門冬胺酸214對於催化反應具有顯著的影響。我們在本文闡明關鍵胺基酸在酵素催化中的功用，這些結論有助於設計與開發新的hapalindole型生物鹼。

摘要(英)

The hapalindole family of alkaloids is a structurally diverse class of natural cyanobacterial products and is active against a broad range of targets, such as antibacterial and antimitotic activities. These complex metabolites are generated by the Stig cyclases in three sequential reactions: Cope rearrangement, 6-exo-trig cyclization, and electrophilic aromatic substitution.
Nevertheless, the enzymatic mechanism of Stig cyclases for catalyzing the rate-determining step of Cope rearrangement has not yet been fully solved. In this study, we have elucidated the enzymatic-catalyzed mechanism of Cope rearrangement reaction of FamC1 by hybrid quantum mechanics/molecular mechanics (QM/MM) molecular dynamics (MD) simulations in conjunction with umbrella sampling (US). We find that the Asp214, assisted by hydrogen-bonded Tyr89 and water, provides the proton source for catalyzing the Cope rearrangement. The Cope rearrangement is occurred through an ionic mechanism rather than the common concerted mechanism. The first bond breaking in the substrate is occurred in company with the proton transfer from the Asp214 yielding one cationic geranyl and one neutral indole ring fragments. More importantly, cation-pi interactions between Phe88 and cationic geranyl fragment and pi-pi interactions between Tyr101 and indole ring forming a “four-layered sandwich” structure stabilize the intermediate within FamC1 protein matrix. Key residue such as Phe88, which crucially determines the rate of the Cope rearrangement, is first recognized. Our proposed enzymatic–catalyzed mechanism clarifies the crucial roles of some key residues and thus provides clues for engineering enzymes for the rare Cope rearrangement.

關鍵字(中)

★ 計算化學
★ 酵素機制

關鍵字(英)

論文目次

摘要 i
Abstract ii
Contents iv
List of Figures v
Chapter 1: Introduction 1
Chapter 2: Methodology 7
2-1 Umbrella sampling method 7
2-2 Structure of FamC1:Substrate(S) Construction 9
2-3 QM/MM MD Simulations with Umbrella Sampling 11
2-4 Density Functional Theory (DFT) calculations 13
Chapter 3: Results and Discussion 14
3-1 Energy Profile of Cope Rearrangement of (R)-3-geranyl-3-isocyanovinyl indolenine within FamC1 14
3-2 Enzymatic-Catalyzed Mechanism of Cope Rearrangement of (R)-3-geranyl-3-isocyanovinyl indolenine within FamC1 18
3-3 Y89 and Water facilitate Proton Transfer for Catalyzing Cope Rearrangement 25
3-4 Cation -p Interactions Stabilize the Intermediate 30
3-5 p -p Interactions Stabilize the Intermediate 36
Chapter 4: Conclusion and Summary 40
References 42
Supporting information 47

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指導教授

蔡惠旭(Hui-Hsu Gavin Tsai)

審核日期

2022-1-21

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