title: Highly potent bisphosphonate ligands for phosphoglycerate kinase.
abstract: We have synthesized a series of novel analogs of 1, 3-bisphospho-D-glyceric acid, 1,3-BPG,3 and evaluated their binding to phosphoglycerate kinase, PGK (EC 2.7.2.3). Nonscissile methanephosphonic acids replace the two phosphate monoesters of 1, 3-BPG and lead to several stable, tight-binding mimics of this intermediate species in glycolysis. Multiple fluorine substitution for hydrogen in the alpha-methylene groups of the phosphonic acid 1, 3-BPG analogs markedly improves their binding to PGK as determined by NMR analysis. The best ligands bind some 50-100 times more strongly than does the substrate 3-phospho-D-glyceric acid and show a requirement for pKa3 to be generally below 6.0, while the presence of a beta-carbonyl group seems to be of secondary importance.
authors.affiliation: Krebs Institute, Department of Chemistry, University of Sheffield, Sheffield, S3 7HF, UK.
authors.forename: D L
authors.initials: DL
authors.lastname: Jakeman
authors.forename: A J
authors.initials: AJ
authors.lastname: Ivory
authors.forename: M P
authors.initials: MP
authors.lastname: Williamson
authors.forename: G M
authors.initials: GM
authors.lastname: Blackburn
mesh_terms: D004163:Diphosphoglyceric Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004164:Diphosphonates / Q000138:chemical synthesis* / Q000378:metabolism; D005988:Glyceric Acids / Q000378:metabolism; D006860:Hydrogen Bonding; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D010735:Phosphoglycerate Kinase / Q000378:metabolism*; D011485:Protein Binding; D013329:Structure-Activity Relationship; D015003:Yeasts / Q000201:enzymology
chemical_list: D004163:Diphosphoglyceric Acids; D004164:Diphosphonates; D005988:Glyceric Acids; D008024:Ligands; C005156:3-phosphoglycerate; D010735:Phosphoglycerate Kinase