The Catalytic Mechanism of the Marine-Derived Macrocyclase PatGmac

被引:16
|
作者
Bras, Natercia F. [1 ]
Ferreira, Pedro [1 ]
Calixto, Ana R. [1 ]
Jaspars, Marcel [2 ]
Houssen, Wael [3 ,4 ]
Naismith, James H. [5 ]
Fernandes, Pedro A. [1 ]
Ramos, Maria J. [1 ]
机构
[1] Univ Porto, UCIBIO, REQUIMTE, Dept Quim & Bioquim,Fac Ciencias, Rua Campo Alegre S-N, P-4169007 Oporto, Portugal
[2] Univ Aberdeen, Marine Biodiscovery Ctr, Dept Chem, Old Aberdeen AB24 3UE, Scotland
[3] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland
[4] Mansoura Univ, Fac Pharm, Dept Pharmacognosy, Mansoura 35516, Egypt
[5] Univ St Andrews, Biomed Sci Res Complex, St Andrews KY16 9ST, Fife, Scotland
基金
英国生物技术与生命科学研究理事会;
关键词
cyclization; molecular mechanics; peptides; quantum mechanics; reaction mechanisms; PEPTIDE MACROCYCLIZATION; NATURAL-PRODUCTS; QM/MM; THERMOCHEMISTRY; PROTEASE;
D O I
10.1002/chem.201601670
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
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(-1) and 19.8 kcal mol(-1) respectively), 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.
引用
收藏
页码:13089 / 13097
页数:9
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