title: Metal Fluorides: Tools for Structural and Computational Analysis of Phosphoryl Transfer Enzymes.
abstract: The phosphoryl group, PO3-, is the dynamic structural unit in the biological chemistry of phosphorus. Its transfer from a donor to an acceptor atom, with oxygen much more prevalent than nitrogen, carbon, or sulfur, is at the core of a great majority of enzyme-catalyzed reactions involving phosphate esters, anhydrides, amidates, and phosphorothioates. The serendipitous discovery that the phosphoryl group could be labeled by "nuclear mutation," by substitution of PO3-by MgF3-or AlF4-, has underpinned the application of metal fluoride (MFx) complexes to mimic transition states for enzymatic phosphoryl transfer reactions, with sufficient stability for experimental analysis. Protein crystallography in the solid state and19F NMR in solution have enabled direct observation of ternary and quaternary protein complexes embracing MFxtransition state models with precision. These studies have underpinned a radically new mechanistic approach to enzyme catalysis for a huge range of phosphoryl transfer processes, as varied as kinases, phosphatases, phosphomutases, and phosphohydrolases. The results, without exception, have endorsed trigonal bipyramidal geometry (tbp) for concerted, "in-line" stereochemistry of phosphoryl transfer. QM computations have established the validity of tbp MFxcomplexes as reliable models for true transition states, delivering similar bond lengths, coordination to essential metal ions, and virtually identical hydrogen bond networks. The emergence of protein control of reactant orbital overlap between bond-forming species within enzyme transition states is a new challenging theme for wider exploration.
authors.affiliation: Structural Biology Laboratory, Department of Chemistry, University of York, York, YO31 7YD, UK.|Department of Molecular Biology and Biotechnology, Krebs Institute, University of Sheffield, Sheffield, S10 2TN, UK.
authors.forename: Yi
authors.initials: Y
authors.lastname: Jin
authors.affiliation: ENSCO, Inc., 4849 North Wickham Road, Melbourne, FD, 32940, USA.|Department of Chemistry and Chemical Biology, Indiana University-Purdue University, Indianapolis, IN, 46202, USA.|Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, IN, 46202, USA.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Molt
authors.affiliation: Department of Molecular Biology and Biotechnology, Krebs Institute, University of Sheffield, Sheffield, S10 2TN, UK. g.m.blackburn@sheffield.ac.uk.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Blackburn
mesh_terms: D017607:Aluminum Compounds / Q000737:chemistry / Q000378:metabolism; D005459:Fluorides / Q000737:chemistry / Q000378:metabolism*; D017616:Magnesium Compounds / Q000737:chemistry / Q000378:metabolism; D015394:Molecular Structure; D010720:Phosphines / Q000737:chemistry / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000378:metabolism*; D010770:Phosphotransferases / Q000737:chemistry / Q000378:metabolism*; D017875:Phosphotransferases (Phosphomutases) / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017607:Aluminum Compounds; D017616:Magnesium Compounds; D010720:Phosphines; D010770:Phosphotransferases; D010744:Phosphoric Monoester Hydrolases; D017875:Phosphotransferases (Phosphomutases); D005459:Fluorides
keywords: Enzyme mechanisms; KS-DFT analysis; MF x; Phosphoryl group surrogates; QM/MM computation; Transition state analogs