Back to Search
Start Over
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.
- Source :
-
Journal of the American Chemical Society [J Am Chem Soc] 2020 Mar 11; Vol. 142 (10), pp. 4892-4903. Date of Electronic Publication: 2020 Mar 01. - Publication Year :
- 2020
-
Abstract
- Human ornithine aminotransferase ( h OAT), a pyridoxal 5'-phosphate-dependent enzyme, plays a critical role in the progression of hepatocellular carcinoma (HCC). Pharmacological selective inhibition of h OAT has been shown to be a potential therapeutic approach for HCC. Inspired by the discovery of the nonselective aminotransferase inactivator (1 R ,3 S ,4 S )-3-amino-4-fluoro cyclopentane-1-carboxylic acid ( 1 ), in this work, we rationally designed, synthesized, and evaluated a novel series of fluorine-substituted cyclohexene analogues, thereby identifying 8 and 9 as novel selective h OAT time-dependent inhibitors. Intact protein mass spectrometry and protein crystallography demonstrated 8 and 9 as covalent inhibitors of h OAT, which exhibit two distinct inactivation mechanisms resulting from the difference of a single fluorine atom. Interestingly, they share a similar turnover mechanism, according to the mass spectrometry-based analysis of metabolites and fluoride ion release experiments. Molecular dynamics (MD) simulations and electrostatic potential (ESP) charge calculations were conducted, which elucidated the significant influence of the one-fluorine difference on the corresponding intermediates, leading to two totally different inactivation pathways. The novel addition-aromatization inactivation mechanism for 9 contributes to its significantly enhanced potency, along with excellent selectivity over other aminotransferases.
- Subjects :
- Cyclohexanecarboxylic Acids chemical synthesis
Cyclohexanecarboxylic Acids metabolism
Cyclohexylamines chemical synthesis
Cyclohexylamines metabolism
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors metabolism
Humans
Hydrocarbons, Fluorinated chemical synthesis
Hydrocarbons, Fluorinated metabolism
Models, Chemical
Molecular Docking Simulation
Molecular Dynamics Simulation
Molecular Structure
Ornithine-Oxo-Acid Transaminase chemistry
Ornithine-Oxo-Acid Transaminase metabolism
Protein Binding
Pyridoxal Phosphate chemistry
gamma-Aminobutyric Acid analogs & derivatives
Cyclohexanecarboxylic Acids chemistry
Cyclohexylamines chemistry
Enzyme Inhibitors chemistry
Hydrocarbons, Fluorinated chemistry
Ornithine-Oxo-Acid Transaminase antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-5126
- Volume :
- 142
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of the American Chemical Society
- Publication Type :
- Academic Journal
- Accession number :
- 32114761
- Full Text :
- https://doi.org/10.1021/jacs.0c00193