title: Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states.
abstract: We studied proposed steps for the enzymatic formation of gamma-carboxyglutamic acid by density functional theory (DFT) quantum chemistry. Our results for one potentially feasible mechanism show that a vitamin K alkoxide intermediate can abstract a proton from glutamic acid at the gamma-carbon to form a carbanion and vitamin K epoxide. The hydrated carbanion can then react with CO2 to form gamma-carboxyglutamic acid. Computations at the B3LYP/6-311G** level were used to determine the intermediates and transition states for the overall process. The activation free energy for the gas-phase path is 22 kcal/mol, with the rate-limiting step for the reaction being the attack of the carbanion on CO2. Additional solvation studies, however, indicate that the formation of the carbanion step can be competitive with the CO2 attack step in high-dielectric systems. We relate these computations to the entire vitamin K cycle in the blood coagulation cascade, which is essential for viability of vertebrates.
authors.affiliation: Department of Biochemistry, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Davis
authors.forename: David Deerfield
authors.initials: DD
authors.lastname: Ii
authors.forename: Darrel W
authors.initials: DW
authors.lastname: Stafford
authors.forename: Lee G
authors.initials: LG
authors.lastname: Pedersen
mesh_terms: D015055:1-Carboxyglutamic Acid / Q000096:biosynthesis / Q000138:chemical synthesis; D002245:Carbon Dioxide / Q000737:chemistry / Q000378:metabolism; D019735:Carbon-Carbon Ligases / Q000737:chemistry* / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry; D006873:Hydroquinones / Q000737:chemistry; D008954:Models, Biological; D015394:Molecular Structure; D011789:Quantum Theory; D014812:Vitamin K / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004852:Epoxy Compounds; D006873:Hydroquinones; D014812:Vitamin K; D002245:Carbon Dioxide; D015055:1-Carboxyglutamic Acid; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase; C031927:hydroquinone