ArticleProceedings of the National Academy of Sciences of the United States of America2019
Enzyme annotation for orphan and novel reactions using knowledge of substrate reactive sites.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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43 citing papers in PubMed.
- The history of enzyme evolution embedded in metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
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- Computational tools for nonnatural pathway design: Algorithms, applications, and challenges.Biodesign research · 2025Review
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- Biosynfoni: a biosynthesis-informed and interpretable lightweight molecular fingerprint.Journal of cheminformatics · 2025Article
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- novoStoic2.0: An integrated framework for pathway synthesis, thermodynamic evaluation, and enzyme selection.PLoS computational biology · 2025Article
- RC-GNN: A predictive model of enzyme-reaction pairs.bioRxiv : the preprint server for biology · 2025Article
- Designing pathways for bioproducing complex chemicals by combining tools for pathway extraction and ranking.Nature communications · 2025Article
- CLAIRE: a contrastive learning-based predictor for EC number of chemical reactions.Journal of cheminformatics · 2025Article
- EquilibraTor streamlines molecular dynamics simulations in a single execution.Computational and structural biotechnology journal · 2025Article
- Artificial Intelligence Methods and Models for Retro-Biosynthesis: A Scoping Review.ACS synthetic biology · 2024Article
- Advancements in biotransformation pathway prediction: enhancements, datasets, and novel functionalities in enviPath.Journal of cheminformatics · 2024Article
- High-Throughput Proteomics Enabled by a Fully Automated Dual-Trap and Dual-Column LC-MS.Analytical chemistry · 2024Article
- Computer-aided design and implementation of efficient biosynthetic pathways to produce high added-value products derived from tyrosine inFrontiers in bioengineering and biotechnology · 2024Article
- From microbiome composition to functional engineering, one step at a time.Microbiology and molecular biology reviews : MMBR · 2023Review
- EnzymeMap: curation, validation and data-driven prediction of enzymatic reactions.Chemical science · 2023Article
- An explainability framework for deep learning on chemical reactions exemplified by enzyme-catalysed reaction classification.Journal of cheminformatics · 2023Article
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5 authors.
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No grant is acknowledged in the PubMed record.
Abstract
Thousands of biochemical reactions with characterized activities are "orphan," meaning they cannot be assigned to a specific enzyme, leaving gaps in metabolic pathways. Novel reactions predicted by pathway-generation tools also lack associated sequences, limiting protein engineering applications. Associating orphan and novel reactions with known biochemistry and suggesting enzymes to catalyze them is a daunting problem. We propose the method BridgIT to identify candidate genes and catalyzing proteins for these reactions. This method introduces information about the enzyme binding pocket into reaction-similarity comparisons. BridgIT assesses the similarity of two reactions, one orphan and one well-characterized nonorphan reaction, using their substrate reactive sites, their surrounding structures, and the structures of the generated products to suggest enzymes that catalyze the most-similar nonorphan reactions as candidates for also catalyzing the orphan ones. We performed two large-scale validation studies to test BridgIT predictions against experimental biochemical evidence. For the 234 orphan reactions from the Kyoto Encyclopedia of Genes and Genomes (KEGG) 2011 (a comprehensive enzymatic-reaction database) that became nonorphan in KEGG 2018, BridgIT predicted the exact or a highly related enzyme for 211 of them. Moreover, for 334 of 379 novel reactions in 2014 that were later cataloged in KEGG 2018, BridgIT predicted the exact or highly similar enzymes. BridgIT requires knowledge about only four connecting bonds around the atoms of the reactive sites to correctly annotate proteins for 93% of analyzed enzymatic reactions. Increasing to seven connecting bonds allowed for the accurate identification of a sequence for nearly all known enzymatic reactions.
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