Inhibition of fructose bisphosphatase and stimulation of phosphofructokinase by a stable isosteric phosphonate analog of fructose 2,6-bisphosphate |
| |
| Authors: | R W McClard S Tsimikas K E Schriver |
| |
| Affiliation: | 1. Oregon Health & Science University, Portland, Oregon;2. Columbia University Irving Medical Center, New York, New York;3. Cardiovascular Division, Brigham and Women''s Hospital, Harvard Medical School, Boston, Massachusetts;4. Hospital Universitário Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil;5. Centro Hospitalar Universitário Lisboa-Norte, Hospital de Santa Maria, Lisbon, Portugal;6. Amyloidosis Center and Department of Neurology, Heidelberg University Hospital, Heidelberg, Germany;7. Boston University School of Medicine, Boston, Massachusetts;8. Mayo Clinic, Rochester, Minnesota;9. National Amyloidosis Centre, University College London, London, UK;10. BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden;11. BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland;12. Ionis Pharmaceuticals, Inc., Carlsbad, California;13. University of California San Diego, La Jolla, California;1. Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico;2. Laboratorio de Fisiopatología Renal, Departamento de Nefrología, Instituto Nacional de Cardiología – Ignacio Chávez, Mexico City, Mexico |
| |
| Abstract: | We describe the synthesis of a mixture of D-manno- and D-gluco-2,5-anhydro-1-deoxy-1-phosphonohexitol 6-phosphate via a Horner-Emmons reaction of 2,3,5-tri-O-benzyl-beta-D-arabinofuranose followed by phosphorylation of the equivalent 6-position and subsequent deprotection. This mixture inhibits fructose-1,6-bisphosphatase; the concentration required for half-maximal effect in the presence of 25 microM AMP is approximately 6 microM. The mixture of analogs also stimulates 6-phosphofructo-1-kinase from rabbit liver; the concentration required to reach one-half Vmax was found to be ca. 25 microM at 0.25 mM fructose 6-phosphate and 50 microM AMP. These analogs have replaced the labile anomeric phosphate of fructose 2,6-bisphosphate with a stable methylenephosphonate, and could be of great interest due to their appropriate physiological effects and their chemical stability. |
| |
| Keywords: | |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
