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@ARTICLE{Rindfleisch:482580,
author = {Rindfleisch, Soeren and Krull, Matthias and Uranga, Jon and
Schmidt, Tobias and Rabe von Pappenheim, Fabian and Kirck,
Laura Liliana and Balouri, Angeliki and Schneider, Thomas
and Chari, Ashwin and Kluger, Ronald and Bourenkov, Gleb and
Diederichsen, Ulf and Mata, Ricardo A. and Tittmann, Kai},
title = {{G}round-state destabilization by electrostatic repulsion
is not a driving force in orotidine-5′-monophosphate
decarboxylase catalysis},
journal = {Nature catalysis},
volume = {5},
number = {4},
issn = {2520-1158},
address = {[London]},
publisher = {Macmillan Publishers Limited, part of Springer Nature},
reportid = {PUBDB-2022-04841},
pages = {332 - 341},
year = {2022},
abstract = {The origins of enzyme catalysis have been attributed to
both transition-state stabilization as well as ground-state
destabilization of the substrate. For the latter paradigm,
the enzyme orotidine-5′-monophosphate decarboxylase
(OMPDC) serves as a reference system as it contains a
negatively charged residue at the active site that is
thought to facilitate catalysis by exerting an electrostatic
stress on the substrate carboxylate leaving group. Snapshots
of how the substrate binds to the active site and interacts
with the negative charge have remained elusive. Here we
present crystallographic snapshots of human OMPDC in complex
with the substrate, substrate analogues, transition-state
analogues and product that defy the proposed ground-state
destabilization by revealing that the substrate carboxylate
is protonated and forms a favourable low-barrier hydrogen
bond with a negatively charged residue. The catalytic
prowess of OMPDC almost entirely results from the
transition-state stabilization by electrostatic interactions
of the enzyme with charges spread over the substrate. Our
findings bear relevance for the design of (de)carboxylase
catalysts.},
cin = {EMBL-User / EMBL},
ddc = {540},
cid = {I:(DE-H253)EMBL-User-20120814 / I:(DE-H253)EMBL-20120731},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3)},
pid = {G:(DE-HGF)POF4-6G3},
experiment = {EXP:(DE-H253)P-P13-20150101 / EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
UT = {WOS:000784635500001},
doi = {10.1038/s41929-022-00771-w},
url = {https://bib-pubdb1.desy.de/record/482580},
}