Time-dependent inhibition of PHD2
| Autor: | Charles E. Grimshaw, Isabelle Tcholakov, Lihong Shi, Kiryanov Andre A, Artur Plonowski, Murphy Sean, Jacques Ermolieff, Christopher J. Larson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
hypoxia inducible factor Cell Biophysics Biochemistry Hypoxia-Inducible Factor-Proline Dioxygenases Small Molecule Libraries 03 medical and health sciences Dissociation rate constant Catalytic Domain medicine Humans Proline liquid chromatography-tandem mass spectrometry time-dependent inhibition Enzyme Inhibitors Molecular Biology Research Articles residence time biology Chemistry hypoxia Active site Cell Biology prolyl hydroxylase 2 Hypoxia (medical) Small molecule Kinetics 030104 developmental biology medicine.anatomical_structure Hypoxia-inducible factors biology.protein Ketoglutaric Acids medicine.symptom Hypoxic stress Research Article Protein Binding |
| Zdroj: | Bioscience Reports |
| ISSN: | 1573-4935 0144-8463 |
| Popis: | Prolyl hydroxylases (PHDs) down-regulate the level of hypoxia-inducible factors (HIFs) by hydroxylating key proline residues that trigger the degradation of the protein and affect the cell and its ability to respond to hypoxic stress. Several small molecule PHD inhibitors are now in various preclinical and clinical stages for the treatment of anemia. The present study provides a detail kinetic analysis for some of these inhibitors. The data generated in the present study suggest that these compounds are reversible and compete directly with the co-substrate, 2-oxoglutarate (2-OG) for binding at the enzyme active site. Most of these compounds are pan PHD inhibitors and exhibit a time-dependent inhibition (TDI) mechanism due to an extremely slow dissociation rate constant, koff, and a long residence time. |
| Databáze: | OpenAIRE |
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