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马来酰亚胺偶联 N 端半胱氨酸肽的序列敏感性和 pH 值依赖性与噻嗪重排反应。

Sequence sensitivity and pH dependence of maleimide conjugated N-terminal cysteine peptides to thiazine rearrangement.

机构信息

Research and Development Department, Bachem Americas, Inc., Torrance, California, USA.

CMC Development Group, Bachem Americas, Inc., Torrance, California, USA.

出版信息

J Pept Sci. 2021 Jul;27(7):e3323. doi: 10.1002/psc.3323. Epub 2021 Mar 30.

DOI:10.1002/psc.3323
PMID:33786923
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8243948/
Abstract

Thiazine formation during the conjugation of N-terminal cysteine peptides to maleimides is an underreported side reaction in the peptide literature. When the conjugation was performed at neutral and basic pH, we observed the thiazine isomer as a significant by-product. Nuclear magnetic resonance (NMR) spectroscopy confirmed the structure of the six-membered thiazine and ultra-high performance liquid chromatography (UHPLC) combined with tandem mass spectrometry (MS/MS) allowed for facile, unambiguous detection due to a unique thiazine mass fragment. Furthermore, substitution of various amino acids adjacent to the N-terminal cysteine in a tripeptide model system resulted in different rates of thiazine formation, albeit within the same order of magnitude. We also determined that varying the N-substitution of the maleimide affects the thiazine conversion rate. Altogether, our findings suggest that thiazine rearrangement for N-terminal cysteine-maleimide adducts is a general side reaction that is applicable to other peptide or protein systems. Performing the conjugation reaction under acidic conditions or avoiding the use of an N-terminal cysteine with a free amino group prevents the formation of the thiazine impurity.

摘要

噻嗪的形成在 N-端半胱氨酸肽与马来酰亚胺的共轭过程中是肽文献中报道较少的副反应。当在中性和碱性 pH 下进行共轭时，我们观察到噻嗪异构体是一个重要的副产物。核磁共振（NMR）光谱证实了六元噻嗪的结构，超高效液相色谱（UHPLC）结合串联质谱（MS/MS）由于独特的噻嗪质量碎片而允许进行简单、明确的检测。此外，在三肽模型系统中，取代 N-端半胱氨酸附近的各种氨基酸会导致噻嗪形成的速率不同，但在同一数量级内。我们还确定了马来酰亚胺的 N-取代变化会影响噻嗪的转化率。总之，我们的研究结果表明，N-端半胱氨酸-马来酰亚胺加合物的噻嗪重排是一种普遍的副反应，适用于其他肽或蛋白质系统。在酸性条件下进行共轭反应或避免使用带有游离氨基的 N-端半胱氨酸可以防止噻嗪杂质的形成。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/eab9d9a2f567/PSC-27-e3323-g013.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/6e7f324301a7/PSC-27-e3323-g012.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/11063cea3631/PSC-27-e3323-g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/eab9d9a2f567/PSC-27-e3323-g013.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/d4a78cbee45a/PSC-27-e3323-g014.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/78a87f4bcdff/PSC-27-e3323-g011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/ecd8653a4683/PSC-27-e3323-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/7dec1ebb7efe/PSC-27-e3323-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/102bb646ccf8/PSC-27-e3323-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/73c009d324b1/PSC-27-e3323-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/5d5d16a77523/PSC-27-e3323-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/6e7f324301a7/PSC-27-e3323-g012.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/782ca4506801/PSC-27-e3323-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/11063cea3631/PSC-27-e3323-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/ea7e8dd09cbc/PSC-27-e3323-g010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/1e443bf2fad5/PSC-27-e3323-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5abf/8243948/eab9d9a2f567/PSC-27-e3323-g013.jpg

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