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Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction.
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-20 , DOI: 10.1038/s41467-019-08833-7 Hiroshi Nonaka 1 , Yuki Nakanishi 1 , Satoshi Kuno 1 , Tomoki Ota 1 , Kentaro Mochidome 1 , Yutaro Saito 1 , Fuminori Sugihara 2 , Yoichi Takakusagi 3, 4 , Ichio Aoki 3, 4 , Satoru Nagatoishi 5, 6 , Kouhei Tsumoto 5, 6 , Shinsuke Sando 1, 6
Nature Communications ( IF 14.7 ) Pub Date : 2019-02-20 , DOI: 10.1038/s41467-019-08833-7 Hiroshi Nonaka 1 , Yuki Nakanishi 1 , Satoshi Kuno 1 , Tomoki Ota 1 , Kentaro Mochidome 1 , Yutaro Saito 1 , Fuminori Sugihara 2 , Yoichi Takakusagi 3, 4 , Ichio Aoki 3, 4 , Satoru Nagatoishi 5, 6 , Kouhei Tsumoto 5, 6 , Shinsuke Sando 1, 6
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Serine hydroxymethyltransferase (SHMT) is an enzyme that catalyzes the reaction that converts serine to glycine. It plays an important role in one-carbon metabolism. Recently, SHMT has been shown to be associated with various diseases. Therefore, SHMT has attracted attention as a biomarker and drug target. However, the development of molecular probes responsive to SHMT has not yet been realized. This is because SHMT catalyzes an essential yet simple reaction; thus, the substrates that can be accepted into the active site of SHMT are limited. Here, we focus on the SHMT-catalyzed retro-aldol reaction rather than the canonical serine-glycine conversion and succeed in developing fluorescent and 19F NMR molecular probes. Taking advantage of the facile and direct detection of SHMT, the developed fluorescent probe is used in the high-throughput screening for human SHMT inhibitors, and two hit compounds are obtained.
中文翻译：
基于逆羟醛型反应的丝氨酸羟甲基转移酶探针设计策略。
丝氨酸羟甲基转移酶（SHMT）是一种催化将丝氨酸转化为甘氨酸的反应的酶。它在一碳代谢中起着重要作用。最近，SHMT 已被证明与多种疾病有关。因此，SHMT作为生物标志物和药物靶点引起了人们的关注。然而，响应SHMT的分子探针的开发尚未实现。这是因为 SHMT 催化了一个重要但简单的反应；因此，能够被SHMT活性位点接受的底物是有限的。在这里，我们专注于 SHMT 催化的逆羟醛反应而不是经典的丝氨酸-甘氨酸转化，并成功开发了荧光和 19F NMR 分子探针。利用SHMT简便、直接检测的优点，将开发的荧光探针用于人SHMT抑制剂的高通量筛选，获得了两个命中化合物。
更新日期：2019-02-20
中文翻译：
基于逆羟醛型反应的丝氨酸羟甲基转移酶探针设计策略。
丝氨酸羟甲基转移酶（SHMT）是一种催化将丝氨酸转化为甘氨酸的反应的酶。它在一碳代谢中起着重要作用。最近，SHMT 已被证明与多种疾病有关。因此，SHMT作为生物标志物和药物靶点引起了人们的关注。然而，响应SHMT的分子探针的开发尚未实现。这是因为 SHMT 催化了一个重要但简单的反应；因此，能够被SHMT活性位点接受的底物是有限的。在这里，我们专注于 SHMT 催化的逆羟醛反应而不是经典的丝氨酸-甘氨酸转化，并成功开发了荧光和 19F NMR 分子探针。利用SHMT简便、直接检测的优点，将开发的荧光探针用于人SHMT抑制剂的高通量筛选，获得了两个命中化合物。
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