ArticleJournal of the American Chemical Society2016
Catalytic Promiscuity of Ancestral Esterases and Hydroxynitrile Lyases.
Article in Journal of the American Chemical Society, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 120 citations in OpenAlex.
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- Substrate scope of ancestral versus modern family-1 glycosidases.Protein science : a publication of the Protein Society · 2026Article
- Ancestral Protein Reconstruction Uncovers a Thermotolerant Rieske Oxygenase with EnhancedACS synthetic biology · 2026Article
- Advances and opportunities for computational interrogation of plant proteins.The Plant journal : for cell and molecular biology · 2026Review
- Buffer-Mediated Catalyst-Free Strecker Reaction Toward Enzymatic Implementation.ChemistryOpen · 2025Article
- Crystal structure of a seven-substitution mutant of hydroxynitrile lyase from rubber tree.Acta crystallographica. Section F, Structural biology communications · 2025Article
- How enzyme functions evolve: genetic, structural, and kinetic perspectives.Biophysical reviews · 2025Review
- Engineering the Reaction Pathway of a Non-heme Iron Oxygenase Using Ancestral Sequence Reconstruction.Journal of the American Chemical Society · 2024Article
- Design of ancestral mammalian alkaline phosphatase bearing high stability and productivity.Applied and environmental microbiology · 2024Article
- Function and Evolution of the Plant MES Family of Methylesterases.Plants (Basel, Switzerland) · 2024Review
- Applications of ancestral sequence reconstruction for understanding the evolution of plant specialized metabolism.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Ancestral Sequence Reconstruction to Enable Biocatalytic Synthesis of Azaphilones.Journal of the American Chemical Society · 2024Article
- Harnessing conformational dynamics in enzyme catalysis to achieve nature-like catalytic efficiencies: the shortest path map tool for computational enzyme redesign.Faraday discussions · 2024Article
- Following the Evolutionary Paths of Dscam1 Proteins toward Highly Specific Homophilic Interactions.Molecular biology and evolution · 2024Article
- Towards Chemoenzymatic Syntheses of Both Enantiomers of Phosphoemeriamine.Molecules (Basel, Switzerland) · 2024Article
- Multifunctional Biocatalysts for Organic Synthesis.Journal of the American Chemical Society · 2024Review
- Non-Native Site-Selective Enzyme Catalysis.Chemical reviews · 2023Review
- Decoupling of catalysis and transition state analog binding from mutations throughout a phosphatase revealed by high-throughput enzymology.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Deciphering the evolution of flavin-dependent monooxygenase stereoselectivity using ancestral sequence reconstruction.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Catalytic promiscuity is a useful, but accidental, enzyme property, so finding catalytically promiscuous enzymes in nature is inefficient. Some ancestral enzymes were branch points in the evolution of new enzymes and are hypothesized to have been promiscuous. To test the hypothesis that ancestral enzymes were more promiscuous than their modern descendants, we reconstructed ancestral enzymes at four branch points in the divergence hydroxynitrile lyases (HNL's) from esterases ∼ 100 million years ago. Both enzyme types are α/β-hydrolase-fold enzymes and have the same catalytic triad, but differ in reaction type and mechanism. Esterases catalyze hydrolysis via an acyl enzyme intermediate, while lyases catalyze an elimination without an intermediate. Screening ancestral enzymes and their modern descendants with six esterase substrates and six lyase substrates found higher catalytic promiscuity among the ancestral enzymes (P < 0.01). Ancestral esterases were more likely to catalyze a lyase reaction than modern esterases, and the ancestral HNL was more likely to catalyze ester hydrolysis than modern HNL's. One ancestral enzyme (HNL1) along the path from esterase to hydroxynitrile lyases was especially promiscuous and catalyzed both hydrolysis and lyase reactions with many substrates. A broader screen tested mechanistically related reactions that were not selected for by evolution: decarboxylation, Michael addition, γ-lactam hydrolysis and 1,5-diketone hydrolysis. The ancestral enzymes were more promiscuous than their modern descendants (P = 0.04). Thus, these reconstructed ancestral enzymes are catalytically promiscuous, but HNL1 is especially so.
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