物理化学学报
物理化學學報
물이화학학보
ACTA PHYSICO-CHIMICA SINICA
2010年
7期
1965-1975
,共11页
李强根%薛英%郭勇%鄢国森
李彊根%薛英%郭勇%鄢國森
리강근%설영%곽용%언국삼
密度泛函理论%极化连续介质模型%脂肪酰胺水解酶%膦酰化反应%甲基花生四烯基氟代膦酸酯%O-甲基二氧磷基氟
密度汎函理論%極化連續介質模型%脂肪酰胺水解酶%膦酰化反應%甲基花生四烯基氟代膦痠酯%O-甲基二氧燐基氟
밀도범함이론%겁화련속개질모형%지방선알수해매%련선화반응%갑기화생사희기불대련산지%O-갑기이양린기불
Density functional theory%Polarizable continuum model%Fatty acid amide hydrolase%Phosphonylation reaction%Methyl arachidonyl fluorophosphonate%O-methyl methylphosphonofluridate
甲基花生四烯基氟代膦酸酯(MAFP)是脂肪酰胺水解酶(FAAH)的一个抑制剂.FAAH的丝氨酸241(Ser241)-丝氨酸217(Ser217)-赖氨酸142(Lys142)催化三联体被MAFP膦酰化后将导致FAAH失活.本文采用B3LYP/6-311G(d,p)和MP2/6-311G(d,p)方法及一个简化的计算模型体系对这个膦酰化抑制反应进行理论研究.考虑了两种反应途径.Path A涉及FAAH的催化三联体的所有残基,是一个分步的加成-消除过程,形成两性离子的三角双锥中间体,其中第一步反应是决速步骤.在这个反应途径中,Ser217和Lys142对亲核试剂Ser241起到碱催化活化的作用,而Ser217充作Lys142和Ser241之间的桥梁.此外,溶剂中的一个水分子作为Lys142和MAFP间的"氢桥"具有关键的作用,通过给出和接收质子促进了长距离的质子转移.Path B是催化三联体中的残基Lys142被突变为丙氨酸以后的膦酰化反应,也是一个分步过程.水的本体溶剂效应通过极化连续介质模型(PCM)估算.计算结果显示膦酰化反应的Path A是优势途径,在水溶液中其决速步骤的活化能垒为64.9 kJ·mol-1.FAAH催化三联体中残基Lys142的变异会降低膦酰化反应的速率,这与实验结果相一致.
甲基花生四烯基氟代膦痠酯(MAFP)是脂肪酰胺水解酶(FAAH)的一箇抑製劑.FAAH的絲氨痠241(Ser241)-絲氨痠217(Ser217)-賴氨痠142(Lys142)催化三聯體被MAFP膦酰化後將導緻FAAH失活.本文採用B3LYP/6-311G(d,p)和MP2/6-311G(d,p)方法及一箇簡化的計算模型體繫對這箇膦酰化抑製反應進行理論研究.攷慮瞭兩種反應途徑.Path A涉及FAAH的催化三聯體的所有殘基,是一箇分步的加成-消除過程,形成兩性離子的三角雙錐中間體,其中第一步反應是決速步驟.在這箇反應途徑中,Ser217和Lys142對親覈試劑Ser241起到堿催化活化的作用,而Ser217充作Lys142和Ser241之間的橋樑.此外,溶劑中的一箇水分子作為Lys142和MAFP間的"氫橋"具有關鍵的作用,通過給齣和接收質子促進瞭長距離的質子轉移.Path B是催化三聯體中的殘基Lys142被突變為丙氨痠以後的膦酰化反應,也是一箇分步過程.水的本體溶劑效應通過極化連續介質模型(PCM)估算.計算結果顯示膦酰化反應的Path A是優勢途徑,在水溶液中其決速步驟的活化能壘為64.9 kJ·mol-1.FAAH催化三聯體中殘基Lys142的變異會降低膦酰化反應的速率,這與實驗結果相一緻.
갑기화생사희기불대련산지(MAFP)시지방선알수해매(FAAH)적일개억제제.FAAH적사안산241(Ser241)-사안산217(Ser217)-뢰안산142(Lys142)최화삼련체피MAFP련선화후장도치FAAH실활.본문채용B3LYP/6-311G(d,p)화MP2/6-311G(d,p)방법급일개간화적계산모형체계대저개련선화억제반응진행이론연구.고필료량충반응도경.Path A섭급FAAH적최화삼련체적소유잔기,시일개분보적가성-소제과정,형성량성리자적삼각쌍추중간체,기중제일보반응시결속보취.재저개반응도경중,Ser217화Lys142대친핵시제Ser241기도감최화활화적작용,이Ser217충작Lys142화Ser241지간적교량.차외,용제중적일개수분자작위Lys142화MAFP간적"경교"구유관건적작용,통과급출화접수질자촉진료장거리적질자전이.Path B시최화삼련체중적잔기Lys142피돌변위병안산이후적련선화반응,야시일개분보과정.수적본체용제효응통과겁화련속개질모형(PCM)고산.계산결과현시련선화반응적Path A시우세도경,재수용액중기결속보취적활화능루위64.9 kJ·mol-1.FAAH최화삼련체중잔기Lys142적변이회강저련선화반응적속솔,저여실험결과상일치.
Methyl arachidonyl fluorophosphonate(MAFP)iS an inhibitor of the fatty acid amide hydrolase(FAAH).We studied the phosphonylation reaction of the serine241(Ser241)-serine217(Set217)-lysine142(Lys142)catalytic triad of FAAH bv MAFP.which leads to the loss of FAAH enzyme activity.This theoretical study was carried out by employing the B3LYP/6-311G(d,p)and MP2/6-311G(d,p)methods through a simplified model.Two reaction pathways were considered.Pam A iS a two-step addition-elimination process of the FAAH catalytic triad and the first step (addition process)iS the rate-determining step and involves a zwitterionic trigonal bipyramidal intermediate.In this reaction pathway,both Ser217 and Lysl42 in FAAH contribute to the base-catalyzed activation of the nucleophile Ser241 while Ser217 serves as a bridge between Lys142 and Ser241.In addition,one of the solvent water molecules performs a key role to act as a"hydrogen bridge"connecting the Lys142 residue and MAFP by donating and accepting protons to promote long-range proton transfer.Path B(after mutation of the Lys142 residue to alanine)is also a stepwise process.nle bulk effect of water as a solvent was considered via the polarizable continuum model(PCM).The obtained results show that for this phosphonyladon reaction,Path A is the most favorable mechanism with an activation free energy barrier of 64.9 kJ·mol-1 in aqueous solution.We also conclude that the mutation of the FAAH catalytic triad at the Lys142 residue decreases the rate of phosphonylation.This is in good agreemem with the experimental observation.
