ArticleJournal of the American Chemical Society2015
Cooperative Electrostatic Interactions Drive Functional Evolution in the Alkaline Phosphatase Superfamily.
Article in Journal of the American Chemical Society, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 64 citations in OpenAlex.
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- General Theory of Specific Binding: Insights from a Genetic-Mechano-Chemical Protein Model.Molecular biology and evolution · 2022Article
- Structural insights into choline-O-sulfatase reveal the molecular determinants for ligand binding.Acta crystallographica. Section D, Structural biology · 2022Article
- Substrate Dynamics Contribute to Enzymatic Specificity in Human and Bacterial Methionine Adenosyltransferases.JACS Au · 2021Article
- Loop Dynamics and Enzyme Catalysis in Protein Tyrosine Phosphatases.Journal of the American Chemical Society · 2021Article
- Larger active site in an ancestral hydroxynitrile lyase increases catalytically promiscuous esterase activity.PloS one · 2020Article
- Transition-State Interactions in a Promiscuous Enzyme: Sulfate and Phosphate Monoester Hydrolysis by Pseudomonas aeruginosa Arylsulfatase.Biochemistry · 2019Article
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- Conformational dynamics and enzyme evolution.Journal of the Royal Society, Interface · 2018Review
- Epoxide hydrolysis as a model system for understanding flux through a branched reaction scheme.IUCrJ · 2018Review
- Extending the Nonbonded Cationic Dummy Model to Account for Ion-Induced Dipole Interactions.The journal of physical chemistry letters · 2017Article
- Enzyme Architecture: Modeling the Operation of a Hydrophobic Clamp in Catalysis by Triosephosphate Isomerase.Journal of the American Chemical Society · 2017Article
- De novo active sites for resurrected Precambrian enzymes.Nature communications · 2017Article
- Active Site Hydrophobicity and the Convergent Evolution of Paraoxonase Activity in Structurally Divergent Enzymes: The Case of Serum Paraoxonase 1.Journal of the American Chemical Society · 2017Article
- Article
- Catalytic scaffolds for phosphoryl group transfer.Current opinion in structural biology · 2016Review
- Probing the mechanisms for the selectivity and promiscuity of methyl parathion hydrolase.Philosophical transactions. Series A, Mathematical, physical, and engineering sciences · 2016Article
- Leaving Group Ability Observably Affects Transition State Structure in a Single Enzyme Active Site.Journal of the American Chemical Society · 2016Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
It is becoming widely accepted that catalytic promiscuity, i.e., the ability of a single enzyme to catalyze the turnover of multiple, chemically distinct substrates, plays a key role in the evolution of new enzyme functions. In this context, the members of the alkaline phosphatase superfamily have been extensively studied as model systems in order to understand the phenomenon of enzyme multifunctionality. In the present work, we model the selectivity of two multiply promiscuous members of this superfamily, namely the phosphonate monoester hydrolases from Burkholderia caryophylli and Rhizobium leguminosarum. We have performed extensive simulations of the enzymatic reaction of both wild-type enzymes and several experimentally characterized mutants. Our computational models are in agreement with key experimental observables, such as the observed activities of the wild-type enzymes, qualitative interpretations of experimental pH-rate profiles, and activity trends among several active site mutants. In all cases the substrates of interest bind to the enzyme in similar conformations, with largely unperturbed transition states from their corresponding analogues in aqueous solution. Examination of transition-state geometries and the contribution of individual residues to the calculated activation barriers suggest that the broad promiscuity of these enzymes arises from cooperative electrostatic interactions in the active site, allowing each enzyme to adapt to the electrostatic needs of different substrates. By comparing the structural and electrostatic features of several alkaline phosphatases, we suggest that this phenomenon is a generalized feature driving selectivity and promiscuity within this superfamily and can be in turn used for artificial enzyme design.
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