Frustration and the Kinetic Repartitioning Mechanism of Substrate Inhibition in Enzyme Catalysis

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dc.citation.firstpage6792en_US
dc.citation.issueNumber36en_US
dc.citation.journalTitleThe Journal of Physical Chemistry Ben_US
dc.citation.lastpage6801en_US
dc.citation.volumeNumber126en_US
dc.contributor.authorZhang, Yangyangen_US
dc.contributor.authorChen, Mingchenen_US
dc.contributor.authorLu, Jiajunen_US
dc.contributor.authorLi, Wenfeien_US
dc.contributor.authorWolynes, Peter G.en_US
dc.contributor.authorWang, Weien_US
dc.contributor.orgCenter for Theoretical Biological Physicsen_US
dc.date.accessioned2022-10-28T17:43:02Zen_US
dc.date.available2022-10-28T17:43:02Zen_US
dc.date.issued2022en_US
dc.description.abstractSubstrate inhibition, whereby enzymatic activity decreases with excess substrate after reaching a maximum turnover rate, is among the most elusive phenomena in enzymatic catalysis. Here, based on a dynamic energy landscape model, we investigate the underlying mechanism by performing molecular simulations and frustration analysis for a model enzyme adenylate kinase (AdK), which catalyzes the phosphoryl transfer reaction ATP + AMP ⇋ ADP + ADP. Intriguingly, these reveal a kinetic repartitioning mechanism of substrate inhibition, whereby excess substrate AMP suppresses the population of an energetically frustrated, but kinetically activated, catalytic pathway going through a substrate (ATP)-product (ADP) cobound complex with steric incompatibility. Such a frustrated pathway plays a crucial role in facilitating the bottleneck product ADP release, and its suppression by excess substrate AMP leads to a slow down of product release and overall turnover. The simulation results directly demonstrate that substrate inhibition arises from the rate-limiting product-release step, instead of the steps for populating the catalytically competent complex as often suggested in previous works. Furthermore, there is a tight interplay between the enzyme conformational equilibrium and the extent of substrate inhibition. Mutations biasing to more closed conformations tend to enhance substrate inhibition. We also characterized the key features of single-molecule enzyme kinetics with substrate inhibition effect. We propose that the above molecular mechanism of substrate inhibition may be relevant to other multisubstrate enzymes in which product release is the bottleneck step.en_US
dc.identifier.citationZhang, Yangyang, Chen, Mingchen, Lu, Jiajun, et al.. "Frustration and the Kinetic Repartitioning Mechanism of Substrate Inhibition in Enzyme Catalysis." <i>The Journal of Physical Chemistry B,</i> 126, no. 36 (2022) American Chemical Society: 6792-6801. https://doi.org/10.1021/acs.jpcb.2c03832.en_US
dc.identifier.digitalacs-jpcb-2c03832en_US
dc.identifier.doihttps://doi.org/10.1021/acs.jpcb.2c03832en_US
dc.identifier.urihttps://hdl.handle.net/1911/113767en_US
dc.language.isoengen_US
dc.publisherAmerican Chemical Societyen_US
dc.rightsThis article is distributed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licenseen_US
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.titleFrustration and the Kinetic Repartitioning Mechanism of Substrate Inhibition in Enzyme Catalysisen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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