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Inhibition of a viral prolyl hydroxylase. 2019

Gareth W Langley, and Martine I Abboud, and Christopher T Lohans, and Christopher J Schofield
Chemistry Research Laboratory, Department of Chemistry, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, United Kingdom.

The hydroxylation of prolyl-residues in eukaryotes is important in collagen biosynthesis and in hypoxic signalling. The hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) are drug targets for the treatment of anaemia, while the procollagen prolyl hydroxylases and other 2-oxoglutarate dependent oxygenases are potential therapeutic targets for treatment of cancer, fibrotic disease, and infection. We describe assay development and inhibition studies for a procollagen prolyl hydroxylase from Paramecium bursaria chlorella virus 1 (vCPH). The results reveal HIF PHD inhibitors in clinical trials also inhibit vCPH. Implications for the targeting of the human PHDs and microbial prolyl hydroxylases are discussed.

UI MeSH Term Description Entries
D007656 Ketoglutaric Acids A family of compounds containing an oxo group with the general structure of 1,5-pentanedioic acid. (From Lehninger, Principles of Biochemistry, 1982, p442) Oxoglutarates,2-Ketoglutarate,2-Ketoglutaric Acid,2-Oxoglutarate,2-Oxoglutaric Acid,Calcium Ketoglutarate,Calcium alpha-Ketoglutarate,Ketoglutaric Acid,Oxogluric Acid,alpha-Ketoglutarate,alpha-Ketoglutaric Acid,alpha-Ketoglutaric Acid, Calcium Salt (2:1),alpha-Ketoglutaric Acid, Diammonium Salt,alpha-Ketoglutaric Acid, Dipotassium Salt,alpha-Ketoglutaric Acid, Disodium Salt,alpha-Ketoglutaric Acid, Monopotassium Salt,alpha-Ketoglutaric Acid, Monosodium Salt,alpha-Ketoglutaric Acid, Potassium Salt,alpha-Ketoglutaric Acid, Sodium Salt,alpha-Oxoglutarate,2 Ketoglutarate,2 Ketoglutaric Acid,2 Oxoglutarate,2 Oxoglutaric Acid,Calcium alpha Ketoglutarate,alpha Ketoglutarate,alpha Ketoglutaric Acid,alpha Ketoglutaric Acid, Diammonium Salt,alpha Ketoglutaric Acid, Dipotassium Salt,alpha Ketoglutaric Acid, Disodium Salt,alpha Ketoglutaric Acid, Monopotassium Salt,alpha Ketoglutaric Acid, Monosodium Salt,alpha Ketoglutaric Acid, Potassium Salt,alpha Ketoglutaric Acid, Sodium Salt,alpha Oxoglutarate,alpha-Ketoglutarate, Calcium
D009842 Oligopeptides Peptides composed of between two and twelve amino acids. Oligopeptide
D011393 Procollagen-Proline Dioxygenase A mixed-function oxygenase that catalyzes the hydroxylation of a prolyl-glycyl containing peptide, usually in PROTOCOLLAGEN, to a hydroxyprolylglycyl-containing-peptide. The enzyme utilizes molecular OXYGEN with a concomitant oxidative decarboxylation of 2-oxoglutarate to SUCCINATE. The enzyme occurs as a tetramer of two alpha and two beta subunits. The beta subunit of procollagen-proline dioxygenase is identical to the enzyme PROTEIN DISULFIDE-ISOMERASES. Protocollagen Prolyl Hydroxylase,Procollagen Prolyl 4-Hydroxylase,4-Hydroxylase, Procollagen Prolyl,Dioxygenase, Procollagen-Proline,Hydroxylase, Protocollagen Prolyl,Procollagen Proline Dioxygenase,Procollagen Prolyl 4 Hydroxylase,Prolyl 4-Hydroxylase, Procollagen,Prolyl Hydroxylase, Protocollagen
D006900 Hydroxylation Placing of a hydroxyl group on a compound in a position where one did not exist before. (Stedman, 26th ed) Hydroxylations
D057075 Enzyme Assays Methods used to measure the relative activity of a specific enzyme or its concentration in solution. Typically an enzyme substrate is added to a buffer solution containing enzyme and the rate of conversion of substrate to product is measured under controlled conditions. Many classical enzymatic assay methods involve the use of synthetic colorimetric substrates and measuring the reaction rates using a spectrophotometer. Enzymatic Assays,Indirect Enzymatic Assays,Indirect Enzyme Assays,Assay, Enzymatic,Assay, Enzyme,Assay, Indirect Enzymatic,Assay, Indirect Enzyme,Assays, Enzymatic,Assays, Enzyme,Assays, Indirect Enzymatic,Assays, Indirect Enzyme,Enzymatic Assay,Enzymatic Assay, Indirect,Enzymatic Assays, Indirect,Enzyme Assay,Enzyme Assay, Indirect,Enzyme Assays, Indirect,Indirect Enzymatic Assay,Indirect Enzyme Assay
D017862 Phycodnaviridae A family of DNA plant viruses that infect eukaryotic algae. Algal Viruses,Algal Virus,Virus, Algal,Viruses, Algal
D019032 Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization A mass spectrometric technique that is used for the analysis of large biomolecules. Analyte molecules are embedded in an excess matrix of small organic molecules that show a high resonant absorption at the laser wavelength used. The matrix absorbs the laser energy, thus inducing a soft disintegration of the sample-matrix mixture into free (gas phase) matrix and analyte molecules and molecular ions. In general, only molecular ions of the analyte molecules are produced, and almost no fragmentation occurs. This makes the method well suited for molecular weight determinations and mixture analysis. Laser Desorption-Ionization Mass Spectrometry, Matrix-Assisted,MALD-MS,MALDI,Mass Spectrometry, Matrix-Assisted Laser Desorption-Ionization,Mass Spectroscopy, Matrix-Assisted Laser Desorption-Ionization,Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry,Spectroscopy, Mass, Matrix-Assisted Laser Desorption-Ionization,MALDI-MS,MS-MALD,SELDI-TOF-MS,Surface Enhanced Laser Desorption Ionization Mass Spectrometry,Laser Desorption Ionization Mass Spectrometry, Matrix Assisted,MALDI MS,Mass Spectrometry, Matrix Assisted Laser Desorption Ionization,Mass Spectroscopy, Matrix Assisted Laser Desorption Ionization,Matrix Assisted Laser Desorption Ionization Mass Spectrometry
D064799 Hypoxia-Inducible Factor-Proline Dioxygenases Dioxygenase enzymes that specifically hydroxylate a PROLINE residue on the HYPOXIA-INDUCIBLE FACTOR 1, ALPHA SUBUNIT. They are OXYGEN-dependent enzymes that play an important role in mediating cellular adaptive responses to HYPOXIA. Egl Nine Homolog 1 Protein,Egl Nine Homolog 2 Protein,Egl Nine Homolog 3 Protein,HIF Prolyl-4-Hydroxylase,HIF Prolyl-4-Hydroxylases,Hypoxia-Inducible Factor Prolyl Hydroxylase 1,Hypoxia-Inducible Factor Prolyl Hydroxylase 2,Hypoxia-Inducible Factor Prolyl Hydroxylase 3,Hypoxia-Inducible Factor-Proline Dioxygenase,Dioxygenase, Hypoxia-Inducible Factor-Proline,Dioxygenases, Hypoxia-Inducible Factor-Proline,Factor-Proline Dioxygenase, Hypoxia-Inducible,Factor-Proline Dioxygenases, Hypoxia-Inducible,HIF Prolyl 4 Hydroxylase,HIF Prolyl 4 Hydroxylases,Hypoxia Inducible Factor Proline Dioxygenase,Hypoxia Inducible Factor Proline Dioxygenases,Hypoxia Inducible Factor Prolyl Hydroxylase 1,Hypoxia Inducible Factor Prolyl Hydroxylase 2,Hypoxia Inducible Factor Prolyl Hydroxylase 3,Prolyl-4-Hydroxylase, HIF,Prolyl-4-Hydroxylases, HIF
D064800 Prolyl-Hydroxylase Inhibitors Compounds that inhibit the action of HYDROXYLASES that act on PROLINE to form HYDROXYPROLINE. Proline Dioxygenase Inhibitor,Proline Hydroxylase Inhibitor,Prolyl Hydroxylase Inhibitor,Prolyl-Hydroxylase Inhibitor,Proline Dioxygenase Inhibitors,Proline Hydroxylase Inhibitors,Dioxygenase Inhibitor, Proline,Dioxygenase Inhibitors, Proline,Hydroxylase Inhibitor, Proline,Hydroxylase Inhibitor, Prolyl,Hydroxylase Inhibitors, Proline,Inhibitor, Proline Dioxygenase,Inhibitor, Proline Hydroxylase,Inhibitor, Prolyl Hydroxylase,Inhibitor, Prolyl-Hydroxylase,Inhibitors, Proline Dioxygenase,Inhibitors, Proline Hydroxylase,Inhibitors, Prolyl-Hydroxylase,Prolyl Hydroxylase Inhibitors

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