ArticleProceedings of the National Academy of Sciences of the United States of America2018
Evolutionary repurposing of a sulfatase: A new Michaelis complex leads to efficient transition state charge offset.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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17 citing papers in PubMed, 45 citations in OpenAlex.
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- Structural and evolutionary constraints of organophosphate resistance in dipteran carboxylesterases.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Mechanistic conformational and substrate selectivity profiles emerging in the evolution of enzymes via parallel trajectories.Nature communications · 2024Article
- Ultrahigh-Throughput Enzyme Engineering and Discovery inChemical reviews · 2023Review
- Ultrahigh-Throughput Directed Evolution of a Metal-Free α/β-Hydrolase with a Cys-His-Asp Triad into an Efficient Phosphotriesterase.Journal of the American Chemical Society · 2023Article
- Distal Mutations Shape Substrate-Binding Sites during Evolution of a Metallo-Oxidase into a Laccase.ACS catalysis · 2022Article
- Structural insights into choline-O-sulfatase reveal the molecular determinants for ligand binding.Acta crystallographica. Section D, Structural biology · 2022Article
- Essential Functional Interplay of the Catalytic Groups in Acid Phosphatase.ACS catalysis · 2022Article
- Substrate Dynamics Contribute to Enzymatic Specificity in Human and Bacterial Methionine Adenosyltransferases.JACS Au · 2021Article
- A mechanistic view of enzyme evolution.Protein science : a publication of the Protein Society · 2020Review
- Harnessing Conformational Plasticity to Generate Designer Enzymes.Journal of the American Chemical Society · 2020Review
- Evolution of new enzymes by gene duplication and divergence.The FEBS journal · 2020Review
- Higher-order epistasis shapes the fitness landscape of a xenobiotic-degrading enzyme.Nature chemical biology · 2019Article
- Transition-State Interactions in a Promiscuous Enzyme: Sulfate and Phosphate Monoester Hydrolysis by Pseudomonas aeruginosa Arylsulfatase.Biochemistry · 2019Article
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- Mutations Utilize Dynamic Allostery to Confer Resistance in TEM-1 β-lactamase.International journal of molecular sciences · 2018Article
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11 authors at 3 institutions in 3 countries.
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Abstract
The recruitment and evolutionary optimization of promiscuous enzymes is key to the rapid adaptation of organisms to changing environments. Our understanding of the precise mechanisms underlying enzyme repurposing is, however, limited: What are the active-site features that enable the molecular recognition of multiple substrates with contrasting catalytic requirements? To gain insights into the molecular determinants of adaptation in promiscuous enzymes, we performed the laboratory evolution of an arylsulfatase to improve its initially weak phenylphosphonate hydrolase activity. The evolutionary trajectory led to a 100,000-fold enhancement of phenylphosphonate hydrolysis, while the native sulfate and promiscuous phosphate mono- and diester hydrolyses were only marginally affected (≤50-fold). Structural, kinetic, and in silico characterizations of the evolutionary intermediates revealed that two key mutations, T50A and M72V, locally reshaped the active site, improving access to the catalytic machinery for the phosphonate. Measured transition state (TS) charge changes along the trajectory suggest the creation of a new Michaelis complex (E•S, enzyme-substrate), with enhanced leaving group stabilization in the TS for the promiscuous phosphonate (
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