| First Author | Knobloch G | Year | 2015 |
| Journal | Bioorg Med Chem | Volume | 23 |
| Issue | 12 | Pages | 2819-27 |
| PubMed ID | 25783190 | Mgi Jnum | J:304580 |
| Mgi Id | MGI:6695679 | Doi | 10.1016/j.bmc.2015.02.049 |
| Citation | Knobloch G, et al. (2015) Synthesis of hydrolysis-resistant pyridoxal 5'-phosphate analogs and their biochemical and X-ray crystallographic characterization with the pyridoxal phosphatase chronophin. Bioorg Med Chem 23(12):2819-27 |
| abstractText | 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 79muM, 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 2.75A 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. |
