A computational investigation on the substrate preference of ten-eleven-translocation 2 (TET2).

Physical Chemistry Chemical Physics : PCCP
Junyan LuCheng Luo

Abstract

TET proteins iteratively convert 5-methylcytosine (5mC) into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) in a Fe(ii)/α-ketoglutarate-dependent manner. Our previous biochemical studies revealed that TET proteins are more active on 5mC than on 5hmC and 5fC. However, the source of the substrate preference of TET proteins still remains largely elusive. Here, we investigated the substrate binding and catalytic mechanisms of oxidation reactions mediated by TET2 on different substrates through computational approaches. In accordance with previous experimental reports, our computational results suggest that TET2 can bind to different substrates with comparable binding affinities and the hydrogen abstraction step in the catalytic cycle acts as the rate-limiting step. Further structural characterization of the intermediate structures revealed that the 5-substitution groups on 5hmC and 5fC adopt an unfavorable orientation for hydrogen abstraction, which leads to a higher energy barrier for 5hmC and 5fC (compared to 5mC) and thus a lower catalytic efficiency. In summary, our mechanical insights demonstrate that substrate preference is the intrinsic property of TET proteins and our theoretical calcu...Continue Reading

References

Nov 25, 1993·Nature·E LiR Jaenisch
Jan 15, 2004·Journal of the American Chemical Society·József KaizerLawrence Que
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
May 4, 2004·Critical Reviews in Biochemistry and Molecular Biology·Robert P Hausinger
Jul 9, 2004·Journal of the American Chemical Society·Sam P de VisserSason Shaik
Sep 22, 2005·The Journal of Biological Chemistry·Dong-Hyun LeeTimothy R O'Connor
Jun 5, 2007·Accounts of Chemical Research·Carsten KrebsJ Martin Bollinger
Apr 3, 2009·The Journal of Physical Chemistry. B·Haining LiuJames W Gauld
Apr 18, 2009·Science·Skirmantas Kriaucionis, Nathaniel Heintz
Sep 22, 2010·Journal of Chemical Theory and Computation·Martin B PetersKenneth M Merz
Dec 21, 2010·Experimental Hematology·Fabian MohrVijay P S Rawat
Jan 12, 2011·Proceedings of the National Academy of Sciences of the United States of America·Shengfa Ye, Frank Neese
Oct 18, 2011·Nature Chemical Biology·Guifang JiaChuan He
May 21, 2014·Accounts of Chemical Research·Bo WangDonald G Truhlar
Nov 21, 2014·Nature Chemistry·Martin BachmanShankar Balasubramanian

❮ Previous
Next ❯

Citations

Dec 6, 2016·Nature Chemical Biology·Monica Yun LiuRahul M Kohli
Jul 28, 2017·Acta Pharmacologica Sinica·Shi-En LiuCheng Luo
Dec 14, 2018·Chemical Science·Hedieh Torabifard, G Andrés Cisneros
Feb 10, 2021·Journal of Molecular Biology·Jamie E DeNizioRahul M Kohli
Jul 30, 2021·Journal of the American Chemical Society·Sushma SappaKabirul Islam
Dec 7, 2018·Journal of the American Chemical Society·Uday GhantyRahul M Kohli
Sep 30, 2021·Physical Chemistry Chemical Physics : PCCP·Madison B BergerG Andrés Cisneros

❮ Previous
Next ❯

Related Concepts

Related Feeds

Cardiovascular Disease & TET2

Cardiovascular diseases are the number one cause of deaths globally. Tet methylcytosine dioxygenase 2 (TET2)-mediated hematopoiesis has been implicated in accelerating heart failure. Here is the latest research on cardiovascular diseases and TET2.