ArticleBiochemistry2017
Selective Targeting by a Mechanism-Based Inactivator against Pyridoxal 5'-Phosphate-Dependent Enzymes: Mechanisms of Inactivation and Alternative Turnover.
Article in Biochemistry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 14 papers.
What it found
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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.
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Who cites it
14 citing papers in PubMed, 14 citations in OpenAlex.
- Substrate-bound structures of yeast ALA synthase reveal protein dynamics initiating heme biosynthesis.Science advances · 2026Article
- Inactivation of ornithine aminotransferase by (1Medicinal chemistry research : an international journal for rapid communications on design and mechanisms of action of biologically active agents · 2026Article
- Design, Synthesis, and Mechanistic Studies of (ACS chemical biology · 2024Article
- Structural and Mechanistic Basis for the Inactivation of Human Ornithine Aminotransferase by (3Molecules (Basel, Switzerland) · 2023Article
- Conformational change of organic cofactor PLP is essential for catalysis in PLP-dependent enzymes.BMB reports · 2022Article
- Determination of the pH dependence, substrate specificity, and turnovers of alternative substrates for human ornithine aminotransferase.The Journal of biological chemistry · 2022Article
- Turnover and Inactivation Mechanisms for (Journal of the American Chemical Society · 2021Article
- Remarkable and Unexpected Mechanism for (Journal of the American Chemical Society · 2021Article
- Structural and Kinetic Analyses Reveal the Dual Inhibition Modes of Ornithine Aminotransferase by (1ACS chemical biology · 2021Article
- Mechanism-Based Design of 3-Amino-4-Halocyclopentenecarboxylic Acids as Inactivators of GABA Aminotransferase.ACS medicinal chemistry letters · 2020Article
- (S)-4-Amino-5-phenoxypentanoate designed as a potential selective agonist of the bacterial transcription factor GabR.Protein science : a publication of the Protein Society · 2020Article
- A Remarkable Difference That One Fluorine Atom Confers on the Mechanisms of Inactivation of Human Ornithine Aminotransferase by Two Cyclohexene Analogues of γ-Aminobutyric Acid.Journal of the American Chemical Society · 2020Article
- Mechanism of Inactivation of Ornithine Aminotransferase by (1Journal of the American Chemical Society · 2019Article
- Design and Mechanism of GABA Aminotransferase Inactivators. Treatments for Epilepsies and Addictions.Chemical reviews · 2018Review
Corrections and comments
- Erratum issued
Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Potent mechanism-based inactivators can be rationally designed against pyridoxal 5'-phosphate (PLP)-dependent drug targets, such as ornithine aminotransferase (OAT) or γ-aminobutyric acid aminotransferase (GABA-AT). An important challenge, however, is the lack of selectivity toward other PLP-dependent, off-target enzymes, because of similarities in mechanisms of all PLP-dependent aminotransferase reactions. On the basis of complex crystal structures, we investigate the inactivation mechanism of OAT, a hepatocellular carcinoma target, by (1R,3S,4S)-3-amino-4-fluorocyclopentane-1-carboxylic acid (FCP), a known inactivator of GABA-AT. A crystal structure of OAT and FCP showed the formation of a ternary adduct. This adduct can be rationalized as occurring via an enamine mechanism of inactivation, similar to that reported for GABA-AT. However, the crystal structure of an off-target, PLP-dependent enzyme, aspartate aminotransferase (Asp-AT), in complex with FCP, along with the results of attempted inhibition assays, suggests that FCP is not an inactivator of Asp-AT, but rather an alternate substrate. Turnover of FCP by Asp-AT is also supported by high-resolution mass spectrometry. Amid existing difficulties in achieving selectivity of inactivation among a large number of PLP-dependent enzymes, the obtained results provide evidence that a desirable selectivity could be achieved, taking advantage of subtle structural and mechanistic differences between a drug-target enzyme and an off-target enzyme, despite their largely similar substrate binding sites and catalytic mechanisms.
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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.