The Catalytic Mechanism of the Marine-Derived Macrocyclase PatGmac.
The Catalytic Mechanism of the Marine-Derived Macrocyclase PatGmac.
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海洋来源的大环酶Patgmac的催化机制。
DOI：
10.1002/chem.201601670
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发表时间：
2016-09-05
影响因子：
4.3
通讯作者：
Ramos, Maria J.
中科院分区：
文献类型：
--
作者：
Bras, Natercia F.;Ferreira, Pedro;Calixto, Ana R.;Jaspars, Marcel;Houssen, Wael;Naismith, James H.;Fernandes, Pedro A.;Ramos, Maria J.
环肽是一类具有高治疗潜力的化合物，具有抗肿瘤和抗病毒（包括抗HIV）等生物活性。尽管它们是可取的，但迄今为止尚未实现这些化合物的有效设计和生产。PatG大环化酶结构域催化patellamide大环化的机制已经通过量子力学/分子力学方法学，特别是ONIOM（M06/6 - 311++G（2d，2 p）：ff 94//B3 LYP/6 - 31 G（d）：ff 94）进行了计算研究。本文提出的机制开始于从Ser 783到His 618和从后者到Asp 548的质子转移。Ser 783对底物的亲核攻击导致酰基-酶共价复合物的形成。底物的离去基团Ala-Tyr-Asp-Gly（AYDG）被底物的N末端质子化，导致P1−P1′键断裂。 最后，底物的N末端攻击P1残基，分解酰基-酶复合物形成大环。 酰基-酶复合物的形成和分解具有最高的活化自由能（分别为21.1kcal mol− 1和19.8 kcal mol− 1），这是丝氨酸蛋白酶的典型特征。 了解髌骨酰胺大环化反应的机理，对于该类酶在制药和生物技术领域的应用具有重要意义。
Cyclic peptides are a class of compounds with high therapeutic potential, possessing bioactivities including antitumor and antiviral (including anti‐HIV). Despite their desirability, efficient design and production of these compounds has not been achieved to date. The catalytic mechanism of patellamide macrocyclization by the PatG macrocyclase domain has been computationally investigated by using quantum mechanics/molecular mechanics methodology, specifically ONIOM(M06/6‐311++G(2d,2p):ff94//B3LYP/6‐31G(d):ff94). The mechanism proposed herein begins with a proton transfer from Ser783 to His 618 and from the latter to Asp548. Nucleophilic attack of Ser783 on the substrate leads to the formation of an acyl–enzyme covalent complex. The leaving group Ala‐Tyr‐Asp‐Gly (AYDG) of the substrate is protonated by the substrate's N terminus, leading to the breakage of the P1−P1′ bond. Finally, the substrate's N terminus attacks the P1 residue, decomposing the acyl–enzyme complex forming the macrocycle. The formation and decomposition of the acyl–enzyme complex have the highest activation free energies (21.1 kcal mol−1and 19.8 kcal mol−1respectively), typical of serine proteases. Understanding the mechanism behind the macrocyclization of patellamides will be important to the application of the enzymes in the pharmaceutical and biotechnological industries.
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影响因子：
16.8
作者：
Koehnke, Jesko;Bent, Andrew;Houssen, Wael E.;Zollman, David;Morawitz, Falk;Shirran, Sally;Vendome, Jeremie;Nneoyiegbe, Ada F.;Trembleau, Laurent;Botting, Catherine H.;Smith, Margaret C. M.;Jaspars, Marcel;Naismith, James H.
通讯作者：
Naismith, James H.
影响因子：
5.6
作者：
Ion, Bogdan F.;Bushnell, Eric A. C.;Gauld, James W.
通讯作者：
Gauld, James W.
影响因子：
7.3
作者：
Giordanetto, Fabrizio;Kihlberg, Jan
通讯作者：
Kihlberg, Jan
影响因子：
15
作者：
McIntosh, John A.;Robertson, Charles R.;Schmidt, Eric W.
通讯作者：
Schmidt, Eric W.
影响因子：
5.5
作者：
Alberto, Marta E.;Marino, Tiziana;Russo, Nino
通讯作者：
Russo, Nino