Metal fluorides as analogs for studies on phosphoryl transfer enzymes

In 1994, the protein structure of a transition state analogue for G1, a small G protein, heralded a new field of research into the structure and mechanism of enzymes that manipulate transfer of the phosphoryl (PO3–) group. It was based on a protein complex of GDP and AlF4– that mimicked the transition state for hydrolysis of GTP. The growing list of enzyme structures that embrace metal fluorides, MFx, as ligands that imitate either the phosphoryl group or a phosphate, now exceeds 80 per triennium. They fall into three distinct geometrical classes: (i) Tetrahedral complexes based on BeF3–, mimic ground state phosphates, (ii) Octahedral complexes, primarily AlF4–, mimic “in-line” anionic transition state for phosphoryl transfer, and (iii) Trigonal bipyramidal complexes additionally mimic the tbp stereochemistry of the transition state and are represented by MgF3– and putative AlF30 complexes. Their interpretation has provided a deeper mechanistic understanding of the behavior and role of phosphate monoesters in molecular biology. This review challenges the existence of AlF30 and MgF4= as real species in protein complexes and questions the relevance for enzymes of physical organic chemistry and model studies that are water-based for phosphoryl group transfer. It proposes a new interpretation of the role of general acid-base catalysis