ArticleJournal of the American Chemical Society2014
Substrate deconstruction and the nonadditivity of enzyme recognition.
Article in Journal of the American Chemical Society, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
19 citing papers in PubMed, 23 citations in OpenAlex.
- Structural comparison of substrate-binding pockets of serine β-lactamases in classes A, C, and D.Journal of enzyme inhibition and medicinal chemistry · 2025Review
- A Perspective on the Strategic Application of Deconstruction-Reconstruction in Drug Discovery.Journal of medicinal chemistry · 2025Review
- Article
- Amino Acid-Derived Ionic Chiral Catalysts Enable Desymmetrizing Cross-Coupling to Remote Acyclic Quaternary Stereocenters.Journal of the American Chemical Society · 2023Article
- Conformation-dependent ligand hot spots in the spliceosomal RNA helicase BRR2.Acta crystallographica. Section D, Structural biology · 2023Article
- Class C β-Lactamases: Molecular Characteristics.Clinical microbiology reviews · 2022Review
- Distal Ionic Substrate-Catalyst Interactions Enable Long-Range Stereocontrol: Access to Remote Quaternary Stereocenters through a Desymmetrizing Suzuki-Miyaura Reaction.Journal of the American Chemical Society · 2022Article
- Efficient Hit-to-Lead Searching of Kinase Inhibitor Chemical Space via Computational Fragment Merging.Journal of chemical information and modeling · 2021Article
- Specificity Distorted: Chemical Induction of Biological Paracatalysis.Biochemistry · 2020Article
- Back to the future: Why we need enzymology to build a synthetic metabolism of the future.Beilstein journal of organic chemistry · 2019Review
- Crius: A novel fragment-based algorithm of de novo substrate prediction for enzymes.Protein science : a publication of the Protein Society · 2018Article
- Genomic Enzymology: Web Tools for Leveraging Protein Family Sequence-Function Space and Genome Context to Discover Novel Functions.Biochemistry · 2017Review
- Article
- Role of Loop-Clamping Side Chains in Catalysis by Triosephosphate Isomerase.Journal of the American Chemical Society · 2015Article
- Lessons from Hot Spot Analysis for Fragment-Based Drug Discovery.Trends in pharmacological sciences · 2015Review
- Ligand deconstruction: Why some fragment binding positions are conserved and others are not.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method.Journal of the American Chemical Society · 2015Article
- The role of phosphate in a multistep enzymatic reaction: reactions of the substrate and intermediate in pieces.Journal of the American Chemical Society · 2015Article
- Covalent docking predicts substrates for haloalkanoate dehalogenase superfamily phosphatases.Biochemistry · 2015Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 6 institutions in 2 countries.
Funding
Abstract
Predicting substrates for enzymes of unknown function is a major postgenomic challenge. Substrate discovery, like inhibitor discovery, is constrained by our ability to explore chemotypes; it would be expanded by orders of magnitude if reactive sites could be probed with fragments rather than fully elaborated substrates, as is done for inhibitor discovery. To explore the feasibility of this approach, substrates of six enzymes from three different superfamilies were deconstructed into 41 overlapping fragments that were tested for activity or binding. Surprisingly, even those fragments containing the key reactive group had little activity, and most fragments did not bind measurably, until they captured most of the substrate features. Removing a single atom from a recognized substrate could often reduce catalytic recognition by 6 log-orders. To explore recognition at atomic resolution, the structures of three fragment complexes of the β-lactamase substrate cephalothin were determined by X-ray crystallography. Substrate discovery may be difficult to reduce to the fragment level, with implications for function discovery and for the tolerance of enzymes to metabolite promiscuity. Pragmatically, this study supports the development of libraries of fully elaborated metabolites as probes for enzyme function, which currently do not exist.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
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.