ArticleAngewandte Chemie (International ed. in English)2025
Promiscuity Guided Evolution of Decarboxylative Aldolases for Synthesis of Tertiary γ-Hydroxy Amino Acids.
Article in Angewandte Chemie (International ed. in English), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- Phage-assisted continuous evolution of enzymes for noncanonical tyrosine biosynthesis.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- A Novel Unsupervised Learning Model with Bayesian Hyperparameter Optimization for Predicting Substrates of Promiscuous Enzymes.ACS omega · 2026Article
- Promiscuity-Guided Enzyme Evolution via Substrate Multiplexed Screening.Angewandte Chemie (International ed. in English) · 2026Review
- Phage-assisted continuous evolution of enzymes for noncanonical tyrosine biosynthesis.bioRxiv : the preprint server for biology · 2026Article
- Toward the Chemoenzymatic Synthesis of DNA-Encoded Libraries.ACS central science · 2026Review
- Biocatalytic Synthesis of N-Protected α-Amino Acids through 1,3-Nitrogen Migration by Nonheme Iron Enzymes.Journal of the American Chemical Society · 2025Article
- Active site diversification of a non-canonical amino acid decarboxylase by merging substrate multiplexed screening with computationally guided recombination.Protein science : a publication of the Protein Society · 2025Article
- Diversity-oriented photobiocatalytic synthesis via stereoselective three-component radical coupling.Science (New York, N.Y.) · 2025Article
- Promiscuity Guided Evolution of Decarboxylative Aldolases for Synthesis of Tertiary γ-Hydroxy Amino Acids.Angewandte Chemie (International ed. in English) · 2025Article
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Authors and funding
4 authors.
Funding
Abstract
Many applications of enzymes benefit from activity on structurally diverse substrates. Here, we sought to engineer the decarboxylative aldolase UstD to perform a challenging C-C bond forming reaction with ketone electrophiles. The parent enzyme had only low levels of activity, portending multiple rounds of directed evolution and a possibility that mutations may inadvertently increase the specificity of the enzyme for a single model screening substrate. We show how to intentionally guide UstD towards generality through multi-generational directed evolution using substrate-multiplexed screening (SUMS). Mutations outside of the active site that impact catalytic function were immediately revealed by shifts in promiscuity, even when the overall activity was lower. By re-targeting these distal residues that couple to the active site with saturation mutagenesis, broadly activating mutations were readily identified. When analyzing active site mutants, SUMS identified both specialist enzymes that would have more limited utility as well as generalist enzymes with complementary activity on diverse substrates. These new UstD enzymes catalyze convergent synthesis of non-canonical amino acids bearing tertiary alcohol side chains. This methodology is easy to implement and enables the rapid and effective evolution of enzymes to catalyze desirable new functions.
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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.