Design strategy for serine hydroxymethyltransferase probes based on retro-aldol-type reaction

Abstract

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.

Serine hydroxymethyltransferase controls blood-meal digestion in the midgut of Aedes aegypti mosquitoes

“…Increased SHMT activity is associated with increased demand for DNA synthesis in rapidly proliferating cells [47]. In recent years, SHMT has been shown to be associated with various diseases and has emerged as an important biomarker and drug target [48, 49]. Our previous studies confirmed that SHMT is the target gene of mosquito-specific miR-1174.…”

Structural basis of inhibition of the human serine hydroxymethyltransferase SHMT2 by antifolate drugs

“…SHMT has been shown to be strongly upregulated in cancer cells , which have an increased demand for DNA synthesis , making the enzyme an attractive chemotherapy drug target. In spite of its increasing importance and numerous biochemical and drug development studies, there are still no SHMT inhibitors in clinical use, or in clinical trials .…”

Structural basis for selective inhibition of human serine hydroxymethyltransferase by secondary bile acid conjugate

“…In our previous study, we performed high-throughput screening of inhibitors targeting hSHMT1 utilizing a fluorescent molecular probe for monitoring hSHMT activity ( Nonaka et al., 2019 ); we obtained two specific candidate inhibitors of hSHMT, one of which was glycodeoxycholic acid (Gly-DCA). In this study, we successfully obtained the crystal of hSHMT bound with Gly-DCA.…”

“… (B) ITC profiles of hSHMT1-Gly-DCA and hSHMT2-Gly-DCA interactions. Calorimetric data for hSHMT1 were obtained from our previous report ( Nonaka et al., 2019 ). (C) The binding of Gly-DCA with hSHMT1 or hSHMT2 assessed using differential scanning calorimetry (DSC).…”