Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36

Proceedings of the National Academy of Sciences of the United States of America
Myles B PoulinVern L Schramm

Abstract

Nuclear receptor SET domain containing protein 2 (NSD2) catalyzes the methylation of histone H3 lysine 36 (H3K36). It is a determinant in Wolf-Hirschhorn syndrome and is overexpressed in human multiple myeloma. Despite the relevance of NSD2 to cancer, there are no potent, selective inhibitors of this enzyme reported. Here, a combination of kinetic isotope effect measurements and quantum chemical modeling was used to provide subangstrom details of the transition state structure for NSD2 enzymatic activity. Kinetic isotope effects were measured for the methylation of isolated HeLa cell nucleosomes by NSD2. NSD2 preferentially catalyzes the dimethylation of H3K36 along with a reduced preference for H3K36 monomethylation. Primary Me-(14)C and (36)S and secondary Me-(3)H3, Me-(2)H3, 5'-(14)C, and 5'-(3)H2 kinetic isotope effects were measured for the methylation of H3K36 using specifically labeled S-adenosyl-l-methionine. The intrinsic kinetic isotope effects were used as boundary constraints for quantum mechanical calculations for the NSD2 transition state. The experimental and calculated kinetic isotope effects are consistent with an SN2 chemical mechanism with methyl transfer as the first irreversible chemical step in the reactio...Continue Reading

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Citations

May 18, 2016·Journal of the American Chemical Society·Myles B PoulinVern L Schramm
Aug 23, 2016·Future Medicinal Chemistry·David S RogawskiTomasz Cierpicki
Oct 19, 2016·Clinical Epigenetics·Angel R de Lera, A Ganesan
Dec 21, 2016·ACS Chemical Biology·Christopher F StrattonVern L Schramm
Feb 15, 2017·Cold Spring Harbor Perspectives in Medicine·Richard L BennettJonathan D Licht
Oct 20, 2018·Journal of Cellular and Molecular Medicine·Xue-Liang ZhouJi-Chun Liu
Feb 17, 2019·Chemphyschem : a European Journal of Chemical Physics and Physical Chemistry·Mariusz MichalczykSteve Scheiner
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Mar 28, 2017·Digestive Diseases and Sciences·Jianzhong YeLanjuan Li
Mar 1, 2020·Scientific Reports·Abbas H K Al TemimiJasmin Mecinović
Jan 31, 2020·Frontiers in Genetics·Mattia ZaghiAlessandro Sessa
Dec 13, 2016·Proceedings of the National Academy of Sciences of the United States of America·Joshua A LinscottMinkui Luo
Sep 29, 2020·Frontiers in Cell and Developmental Biology·Fei XuLinjun Chen
Dec 11, 2020·Scientific Reports·Abbas H K Al TemimiJasmin Mecinović
Dec 17, 2020·International Journal of Molecular Sciences·Marijn N MaasJasmin Mecinović
Mar 15, 2020·Progress in Neuro-psychopharmacology & Biological Psychiatry·Wenxin LiuDonghong Cui
Mar 16, 2021·Frontiers in Cell and Developmental Biology·Weidi WangGuan Ning Lin
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Apr 30, 2019·Journal of the American Chemical Society·Shi ChenMinkui Luo
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Dec 17, 2021·Communications Biology·Shiro Iuchi, Joao A Paulo

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