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首页> 外文期刊>Journal of pharmaceutical sciences. >The role of the cyclic imide in alternate degradation pathways for asparagine-containing peptides and proteins.
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The role of the cyclic imide in alternate degradation pathways for asparagine-containing peptides and proteins.

机译：环状酰亚胺在含天冬酰胺的肽和蛋白质的替代降解途径中的作用。

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Peptides and proteins exhibit enhanced reactivity at asparagine residues due to the formation of a reactive succinimide intermediate that produces normal and isoaspartyl deamidation products along with significant racemization. This study examines the potential for attack of amine nucleophiles at the succinimide carbonyls to generate alternate decomposition products, depending on the nucleophile involved in the reaction. The reactions of the model peptides Phe-Asn-Gly (FNG) and Phe-isoAsn-Gly (FisoNG) were explored as a function of pH (8.5-10.5) in the presence and absence of ammonia buffer (0.2-2 M) using an isocratic HPLC method to monitor reactant disappearance and product formation. In addition to deamidation to form isoAsp and Asp peptides, two additional types of reactions were found to occur via the succinimide intermediate under these conditions. Back-reaction of the succinimide with ammonia led to peptide backbone isomerization while intramolecular attack by the amino terminus produced diketopiperazines. A kinetic model assuming a central role for the succinimide intermediate was derived to fit the concentration versus time data. These studies implicate the cyclic imide as a key intermediate in the formation of alternate peptide and protein degradants, including possible covalent amide-linked aggregates that may form from intermolecular attack of the cyclic imide by neighboring amino groups.
机译：肽和蛋白质在天冬酰胺残基上显示出增强的反应性，这是由于形成了反应性的琥珀酰亚胺中间体，该中间体可产生正常的和异天冬氨酰胺脱酰胺产物以及显着的消旋作用。这项研究检查了胺亲核试剂对琥珀酰亚胺羰基的攻击潜能，以产生交替的分解产物，具体取决于反应中涉及的亲核试剂。在存在和不存在氨水缓冲液（0.2-2 M）的情况下，使用pH（8.5-10.5）考察了模型肽Phe-Asn-Gly（FNG）和Phe-isoAsn-Gly（FisoNG）的反应，方法是使用等度HPLC方法，以监测反应物消失和产物形成。除了脱酰胺作用形成isoAsp和Asp肽外，在这些条件下，通过琥珀酰亚胺中间体还发现了另外两种类型的反应。琥珀酰亚胺与氨的背反应导致肽主链异构化，而氨基末端的分子内攻击产生了二酮哌嗪。推导了一个动力学模型，假设该模型对琥珀酰亚胺中间体起着中心作用，以拟合浓度对时间的数据。这些研究暗示环酰亚胺是形成交替的肽和蛋白质降解物的关键中间产物，包括可能的共价酰胺连接的聚集体，这些聚集体可能是由于环酰亚胺受到相邻氨基的分子间攻击而形成的。

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