How equal charges in enzymes control biochemical reactions
Fundamental principle of enzyme catalysis

Date:
April 25, 2022
Source:
University of Go"ttingen
Summary:
It is well known in physics and chemistry that equal charges repel
each other, while opposite charges attract. It was long assumed
that this principle also applies when enzymes -- the biological
catalysts in all living organisms -- form or break chemical bonds.



FULL STORY ==========================================================================
It is well known in physics and chemistry that equal charges repel each
other, while opposite charges attract. It was long assumed that this
principle also applies when enzymes -- the biological catalysts in all
living organisms - - form or break chemical bonds. It was thought that
enzymes place charges in their "active centres," where the chemical
reactions actually take place, in such a way that they repel similar
charges from the other molecules around them. This concept is known as "electrostatic stress." For example, if the substrate (the substance
upon which the enzyme acts) carries a negative charge, the enzyme could
use a negative charge to "stress" the substrate and thus facilitate
the reaction. However, a new study by the University of Go"ttingen and
the Max Planck Institute for Multidisciplinary Sciences in Go"ttingen
has now shown that, contrary to expectations, two equal charges do not necessarily lead to repulsion, but can cause attraction in enzymes. The
results were published in the journal Nature Catalysis.


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The team investigated a well-known enzyme that has been studied
extensively and is a textbook example of enzyme catalysis. Without the
enzyme, the reaction is extremely slow: in fact, it would take 78 million
years for half of the substrate to react. The enzyme accelerates this
reaction by 1017 times, simply by positioning negative and positive
charges in the active centre. Since the substrate contains a negatively
charged group that is split off as carbon dioxide, it was assumed
for decades that the negative charges of the enzyme serve to stress
the substrate, which is also negatively charged, and accelerate the
reaction. However, this hypothetical mechanism remained unproven because
the structure of the reaction was too fast to be observed.

Professor Kai Tittmann's group at the Go"ttingen Center for Molecular Biosciences (GZMB) has now succeeded for the first time in using protein crystallography to obtain a structural snapshot of the substrate shortly
before the chemical reaction. Unexpectedly, the negative charges of
enzyme and substrate did not repel each other. Instead, they shared
a proton, which acted like a kind of molecular glue in an attractive interaction. "The question of whether two equal charges are friends or
foes in the context of enzyme catalysis has long been controversial in
our field, and our study shows that the basic principles of how enzymes
work are still a long way from being understood," says Tittmann. The crystallographic structures were analysed by quantum chemist Professor
Ricardo Mata and his team from Go"ttingen University's Institute of
Physical Chemistry. "The additional proton, which has a positive charge, between the two negative charges is not only used to attract the molecule involved in the reaction, but it triggers a cascade of proton transfer reactions that further accelerate the reaction," Mata explains.

"We believe that these newly described principles of enzyme catalysis
will help in the development of new chemical catalysts," says
Tittmann. "Since the enzyme we studied releases carbon dioxide, the
most important greenhouse gas produced by human activities, our results
could help develop new chemical strategies for carbon dioxide fixation."
The study involved scientists from the Go"ttingen Centre for Molecular Biosciences (GZMB), the Faculty of Biology and Psychology, and the Faculty
of Chemistry at the University of Go"ttingen, as well as the Max Planck Institute for Multidisciplinary Sciences, the European Molecular Biology Laboratory (EMBL) Hamburg and the University of Toronto. The publication
is dedicated to the memory of co-author Professor Ulf Diederichsen,
who passed away last year.


========================================================================== Story Source: Materials provided by University_of_Go"ttingen. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. So"ren Rindfleisch, Matthias Krull, Jon Uranga, Tobias Schmidt,
Fabian
Rabe von Pappenheim, Laura Liliana Kirck, Angeliki Balouri,
Thomas Schneider, Ashwin Chari, Ronald Kluger, Gleb Bourenkov,
Ulf Diederichsen, Ricardo A. Mata, Kai Tittmann. Ground-state
destabilization by electrostatic repulsion is not a driving force
in orotidine-5'- monophosphate decarboxylase catalysis. Nature
Catalysis, 2022; DOI: 10.1038/s41929-022-00771-w ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220425104932.htm

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