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

Nature Communications
Hiroshi NonakaShinsuke Sando

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.

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Citations

Jan 12, 2021·Metabolomics : Official Journal of the Metabolomic Society·Yuko YamaguchiRichard D Semba
Aug 14, 2019·Molecular Metabolism·Matthias PietzkeAlexei Vazquez
Feb 24, 2021·Journal of Medicinal Chemistry·Chihoko YoshimuraKouhei Tsumoto
Mar 3, 2021·Proceedings of the National Academy of Sciences of the United States of America·Chunfang GuStephen B Shears
Apr 17, 2021·ACS Pharmacology & Translational Science·Christine R CuthbertsonNouri Neamati
Aug 28, 2021·Cancers·Angela TramontiJavier A Menendez
Sep 1, 2021·Trends in Biotechnology·Seon-Hwa LeeDeok-Kun Oh

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Methods Mentioned

BETA
ELISA
NMR
X-ray
thermal shift
isothermal titration calorimetry
Fluorescence
PCR

Software Mentioned

ParaVision

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