title: Synthesis of hydrolysis-resistant pyridoxal 5'-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin.
abstract: A set of phosphonic acid derivatives (1-4) of pyridoxal 5'-phosphate (PLP) was synthesized and characterized biochemically using purified murine pyridoxal phosphatase (PDXP), also known as chronophin. The most promising compound 1 displayed primarily competitive PDXP inhibitory activity with an IC50 value of 79μM, which was in the range of the Km of the physiological substrate PLP. We also report the X-ray crystal structure of PDXP bound to compound 3, which we solved to 2.75Å resolution (PDB code 5AES). The co-crystal structure proves that compound 3 binds in the same orientation as PLP, and confirms the mode of inhibition to be competitive. Thus, we identify compound 1 as a PDXP phosphatase inhibitor. Our results suggest a strategy to design new, potent and selective PDXP inhibitors, which may be useful to increase the sensitivity of tumor cells to treatment with cytotoxic agents.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany; Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Knobloch
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany; EMBL Heidelberg, Genome Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
authors.forename: Nauras
authors.initials: N
authors.lastname: Jabari
authors.affiliation: EMBL Heidelberg, Genome Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Stadlbauer
authors.affiliation: Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schindelin
authors.affiliation: EMBL Heidelberg, Genome Biology Unit, Meyerhofstrasse 1, D-69117 Heidelberg, Germany. Electronic address: koehn@embl.de.
authors.forename: Maja
authors.initials: M
authors.lastname: Köhn
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, D-97078 Würzburg, Germany; Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Josef-Schneider-Strasse 2, D-97080 Würzburg, Germany. Electronic address: antje.gohla@virchow.uni-wuerzburg.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Gohla
mesh_terms: D000818:Animals; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006868:Hydrolysis; D051379:Mice; D062105:Molecular Docking Simulation; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011732:Pyridoxal Phosphate; C587629:Pdxp protein, mouse; D010749:Phosphoprotein Phosphatases; D010744:Phosphoric Monoester Hydrolases
keywords: Cancer therapy; Chronophin; Haloacid dehalogenase-type phosphatase; Non-hydrolyzable pyridoxal 5′-phosphate analogs; Pyridoxal 5′-phosphate phosphatase