ArticleProceedings of the National Academy of Sciences of the United States of America2022
Leveraging intrinsic flexibility to engineer enhanced enzyme catalytic activity.
Article in Proceedings of the National Academy of Sciences of the United States of America, 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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Who cites it
18 citing papers in PubMed, 50 citations in OpenAlex.
- Deep Prior Framework: integrating functional specificity with general plausibility for targeted protein evolution.Briefings in bioinformatics · 2026Article
- SegDesign: A modular framework for controllable protein segment engineering.Protein science : a publication of the Protein Society · 2026Article
- Temperature-Dependent Active-Site Rearrangements of PETaseSM14: Insights from Molecular Dynamics Simulations.International journal of molecular sciences · 2026Article
- Dynamic Allostery in T Cell Receptor Specificity: A Role for Peptides and MHC Polymorphisms in Allosterically Tuning Immune Recognition.BioEssays : news and reviews in molecular, cellular and developmental biology · 2026Review
- Decoding the substrate specificity landscape of a promiscuous enzyme through multi-substrate mutational scanning.Nature communications · 2026Article
- Development of a Potent Engineered Microbial Lipase for the Treatment of Exocrine Pancreatic Insufficiency.Gastro hep advances · 2026Article
- Hydrogen-deuterium exchange reveals catalytically linked protein flexibility in myoglobin-mediated intramolecular C(spProtein science : a publication of the Protein Society · 2026Article
- Article
- Promiscuity Guided Evolution of Decarboxylative Aldolases for Synthesis of Tertiary γ-Hydroxy Amino Acids.Angewandte Chemie (International ed. in English) · 2025Article
- Mechanistic Insights into the Stimulatory Effect of Melanogenesis of 4-Methylcoumarin Derivatives in B16F10 Melanoma Cells.International journal of molecular sciences · 2024Article
- A computational strategy to improve the activity of tyrosine phenol-lyase for the synthesis of L-DOPA.Scientific reports · 2024Article
- Mechanistic conformational and substrate selectivity profiles emerging in the evolution of enzymes via parallel trajectories.Nature communications · 2024Article
- Mapping Conformational Changes in the Saliva Proteome Potentially Associated with Oral Cancer Aggressiveness.Journal of proteome research · 2024Article
- C-to-G editing generates double-strand breaks causing deletion, transversion and translocation.Nature cell biology · 2024Article
- Comprehensive analysis of mitochondrial DNA variants, mitochondrial DNA copy number and oxidative damage in psoriatic arthritis.Biomedical reports · 2023Article
- Fundamentals of HDX-MS.Essays in biochemistry · 2023Review
- Rational design of enzyme activity and enantioselectivity.Frontiers in bioengineering and biotechnology · 2023Review
- General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model.Molecular biology and evolution · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Dynamic motions of enzymes occurring on a broad range of timescales play a pivotal role in all steps of the reaction pathway, including substrate binding, catalysis, and product release. However, it is unknown whether structural information related to conformational flexibility can be exploited for the directed evolution of enzymes with higher catalytic activity. Here, we show that mutagenesis of residues exclusively located at flexible regions distal to the active site of Homo sapiens kynureninase (HsKYNase) resulted in the isolation of a variant (BF-HsKYNase) in which the rate of the chemical step toward kynurenine was increased by 45-fold. Mechanistic pre–steady-state kinetic analysis of the wild type and the evolved enzyme shed light on the underlying effects of distal mutations (>10 Å from the active site) on the rate-limiting step of the catalytic cycle. Hydrogen-deuterium exchange coupled to mass spectrometry and molecular dynamics simulations revealed that the amino acid substitutions in BF-HsKYNase allosterically affect the flexibility of the pyridoxal-5′-phosphate (PLP) binding pocket, thereby impacting the rate of chemistry, presumably by altering the conformational ensemble and sampling states more favorable to the catalyzed reaction.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.