ArticleThe journal of physical chemistry. B2022
Frustration and the Kinetic Repartitioning Mechanism of Substrate Inhibition in Enzyme Catalysis.
Article in The journal of physical chemistry. B, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed.
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- Enhanced terpenoid synthesis in Alternaria alstroemeriae PPL7 via co-fermentation with Paeonia lactiflora roots: integrated metabolomic and transcriptomic analysis.Archives of microbiology · 2026Article
- Unique kinetic behavior of a secondary alcohol dehydrogenase: from a reaction engineering point of view.Bioprocess and biosystems engineering · 2026Article
- Allosteric regulation of enzymatic catalysis by molecular crowding.Communications chemistry · 2026Article
- Novel Rapid In Situ Curable PEGDA/PEG Composite Hydrogel Drives Biological Closure of Aneurysm Neck.ACS omega · 2026Article
- Dual-Enzyme Co-Catalysis Strategy for Fructooligosaccharides (FOS) Biocatalytic Synthesis for Valorization of Low-Cost Byproduct Sugarcane Molasses.Foods (Basel, Switzerland) · 2026Article
- Bimetallic Au-Ag Nanoclusters as a Photo-Responsive Oxidase-Like Nanozyme for Antioxidant Detection and Intracellular Redox Analysis.Small science · 2026Article
- Frustration in the protein-protein interface plays a central role in the cooperativity of PROTAC ternary complexes.Nature communications · 2025Article
- Streamlined production of immobilized D-psicose 3-epimerase via secretion in Pichia pastoris: a new paradigm for industrial D-psicose production.Microbial cell factories · 2025Article
- Multiscale Simulation Guided Electric Field-Enhanced Ammonia Catalytic Cracking.ACS catalysis · 2025Article
- β-Carotene alleviates substrate inhibition caused by asymmetric cooperativity.Nature communications · 2025Article
- Photoactive nanocatalysts as DTT-assisted BSA-AuNCs with enhanced oxidase-mimicking ability for sensitive fluorometric detection of antioxidants.Journal of nanobiotechnology · 2024Article
- Analysis of phosphofructokinase-1 activity as affected by pH and ATP concentration.Scientific reports · 2024Article
- Enzyme activation by urea reveals the interplay between conformational dynamics and substrate binding: a single-molecule FRET study.bioRxiv : the preprint server for biology · 2024Article
- The value of protein allostery in rational anticancer drug design: an update.Expert opinion on drug discovery · 2024Review
- Predicting protein conformational motions using energetic frustration analysis and AlphaFold2.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The marionette mechanism of domain-domain communication in the antagonist, agonist, and coactivator responses of the estrogen receptor.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Role of Repeated Conformational Transitions in Substrate Binding of Adenylate Kinase.The journal of physical chemistry. B · 2022Article
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Authors and funding
6 authors.
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Abstract
Substrate 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.
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