无机磷酸盐物种催化位于N末端的谷氨酰胺残基的非酶分子内环化机理的计算研究。,ACS Omega

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无机磷酸盐物种催化位于N末端的谷氨酰胺残基的非酶分子内环化机理的计算研究。
ACS Omega ( IF 3.7 ) Pub Date : 2020-04-13 , DOI: 10.1021/acsomega.9b04384
Tomoki Nakayoshi _{1,

2} , Koichi Kato _{1,

3} , Eiji Kurimoto ₁ , Akifumi Oda _{1,

2,

4}

Affiliation

位于N-末端的谷氨酰胺（Gln）残基经历自发的分子内环化作用，导致焦谷氨酸（pGlu）残基的形成。在各种肽和蛋白质的N端均已检测到pGlu残基。在抗体药物的发酵和纯化过程中，pGlu残留物的形成是这些药物设计和配制中关注的问题之一，据报道在磷酸盐缓冲液中迅速进行。在这项研究中，我们通过使用B3LYP密度泛函方法的量子化学计算，研究了N端Gln残基形成pGlu残基的磷酸盐催化机制。使用二阶Møller-Plesset微扰理论计算单点能量。我们对模型化合物进行了计算，其中不带电荷的N末端Gln残基在C末端带有甲基氨基。pGlu残基形成的活化能经计算为83.8 kJ mol-1，低于典型的氨基酸残基非酶促反应的活化能。另外，计算结果表明，N-末端Gln残基中主链和侧链的柔性对于进行pGlu残基的形成是必需的。在获得的途径中，无机磷酸盐通过介导质子转移充当催化剂。另外，计算结果表明，N-末端Gln残基中主链和侧链的柔性对于进行pGlu残基的形成是必需的。在获得的途径中，无机磷酸盐通过介导质子转移充当催化剂。另外，计算结果表明，N-末端Gln残基中主链和侧链的柔性对于进行pGlu残基的形成是必需的。在获得的途径中，无机磷酸盐通过介导质子转移充当催化剂。

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Computational Studies on the Mechanisms of Nonenzymatic Intramolecular Cyclization of the Glutamine Residues Located at N-Termini Catalyzed by Inorganic Phosphate Species.

Glutamine (Gln) residues located at N-termini undergo spontaneous intramolecular cyclization, causing the formation of pyroglutamic acid (pGlu) residues. pGlu residues have been detected at the N-termini in various peptides and proteins. The formation of pGlu residues during the fermentation and purification processes of antibody drugs is one of the concerns in the design and formulation of these drugs and has been reported to proceed rapidly in a phosphate buffer. In this study, we have examined the phosphate-catalyzed mechanisms of the pGlu residue formation from N-terminal Gln residues via quantum chemical calculations using B3LYP density functional methods. Single-point energies were calculated using the second-order Møller-Plesset perturbation theory. We performed the calculations for the model compound in which an uncharged N-terminal Gln residue is capped with a methyl amino group on the C-terminal. The activation energy of the formation of pGlu residues was calculated as 83.8 kJ mol-1, which was lower than that of the typical nonenzymatic reaction of amino acid residues. In addition, the computational results indicate that the flexibility of the main and side chains in N-terminal Gln residues was necessary for the formation of pGlu residues to proceed. In the obtained pathway, inorganic phosphate species act as the catalyst by mediating the proton transfer.

更新日期：2020-04-23

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