High-Precision Sulfur Metabolomics Innovated by a New Specific Probe for Trapping Reactive Sulfur Species
High-Precision Sulfur Metabolomics Innovated by a New Specific Probe for Trapping Reactive Sulfur Species
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DOI：
10.1089/ars.2020.8073
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发表时间：
2021-01-04
影响因子：
6.6
通讯作者：
Akaike, Takaaki
中科院分区：
文献类型：
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作者：
Kasamatsu, Shingo;Ida, Tomoaki;Akaike, Takaaki
目的：过硫化物和其他活性硫在体内大量内源性产生，参与多种生理和病理条件下的细胞功能。在目前的研究中，我们的目标是开发一种理想的烷基化剂，用于硫代谢组学，特别是针对过硫化物和其他活性硫物种，以最小的人工分解。结果：合成了一种基于酪氨酸的碘乙酰胺衍生物n -碘乙酰基酪氨酸甲酯（TME-IAM），它与半胱氨酸的巯基残基反应与市售试剂β -（4-羟基苯基）乙基碘乙酰胺（HPE-IAM）反应相同。我们之前的研究表明，尽管各种亲电烷基化剂很容易分解多硫化物，但HPE-IAM通过抑制多硫化物的碱性水解来稳定多硫化物。新合成的TME-IAM对氧化谷胱甘肽四硫化物的稳定作用优于其他烷基化剂，包括HPE-IAM、碘乙酰胺和单溴莫烷。事实上，我们的定量硫相关代谢组分析表明，与HPE-IAM相比，TME-IAM是一种更有效的诱捕剂，可捕获小鼠肝脏和脑组织中含有大量硫原子的内源性过硫化物/多硫化物。创新和结论：我们开发了一种新的碘乙酰胺衍生物，这是迄今为止开发的最理想的试剂，用于检测生物样品（如培养细胞、组织和血浆）中形成的内源性过硫化物/多硫化物。该探针可用于研究活性过硫化物的独特化学性质，从而鉴定出由于其不稳定性而尚未鉴定的新型活性硫代谢物，从而可应用于氧化还原生物学和医学中的高精度硫代谢组学。本研究未进行任何临床实验。
Aims: Persulfides and other reactive sulfur species are endogenously produced in large amounts in vivo and participate in multiple cellular functions underlying physiological and pathological conditions. In the current study, we aimed to develop an ideal alkylating agent for use in sulfur metabolomics, particularly targeting persulfides and other reactive sulfur species, with minimal artifactual decomposition.Results: We synthesized a tyrosine-based iodoacetamide derivative, N-iodoacetyl l-tyrosine methyl ester (TME-IAM), which reacts with the thiol residue of cysteine identically to that of beta-(4-hydroxyphenyl)ethyl iodoacetamide (HPE-IAM), a commercially available reagent. Our previous study revealed that although various electrophilic alkylating agents readily decomposed polysulfides, HPE-IAM exceptionally stabilized the polysulfides by inhibiting their alkaline hydrolysis. The newly synthesized TME-IAM stabilizes oxidized glutathione tetrasulfide more efficiently than other alkylating agents, including HPE-IAM, iodoacetamide, and monobromobimane. In fact, our quantitative sulfur-related metabolome analysis showed that TME-IAM is a more efficient trapping agent for endogenous persulfides/polysulfides containing a larger number of sulfur atoms in mouse liver and brain tissues compared with HPE-IAM.Innovation and Conclusions: We developed a novel iodoacetamide derivative, which is the most ideal reagent developed to date for detecting endogenous persulfides/polysulfides formed in biological samples, such as cultured cells, tissues, and plasma. This new probe may be useful for investigating the unique chemical properties of reactive persulfides, thereby enabling identification of novel reactive sulfur metabolites that remain unidentified because of their instability, and thus can be applied in high-precision sulfur metabolomics in redox biology and medicine. We did not perform any clinical experiments in this study.