title: Vitamin K oxygenation, glutamate carboxylation, and processivity: defining the three critical facets of catalysis by the vitamin K-dependent carboxylase.
abstract: The vitamin K-dependent carboxylase uses vitamin K oxygenation to drive carboxylation of multiple glutamates in vitamin K-dependent proteins, rendering them active in a variety of physiologies. Multiple carboxylations of proteins are required for their activity, and the carboxylase is processive, so that premature dissociation of proteins from the carboxylase does not occur. The carboxylase is unique, with no known homology to other enzyme families, and structural determinations have not been made, rendering an understanding of catalysis elusive. Although a model explaining the relationship of oxygenation to carboxylation had been developed, until recently almost nothing was known of the function of the carboxylase itself in catalysis. In the past decade, discovery and analysis of naturally occurring carboxylase mutants has led to identification of functionally relevant residues and domains. Further, identification of nonmammalian carboxylase orthologs has provided a basis for bioinformatic analysis to identify candidates for critical functional residues. Biochemical analysis of rationally chosen carboxylase mutants has led to breakthroughs in understanding vitamin K oxygenation, glutamate carboxylation, and maintenance of processivity by the carboxylase. Protein carboxylation has also been assessed in vivo, and the intracellular environment strongly affects carboxylase function. The carboxylase is an integral membrane protein, and topological analysis, coupled with biochemical determinations, suggests that interaction of the carboxylase with the membrane is an important facet of function. Carboxylase homologs, likely acquired by horizontal transfer, have been discovered in some bacteria, and functional analysis of these homologs has the potential to lead to the discovery of new roles of vitamin K in biology.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic Foundation, OH, USA. rishavm@ccf.org
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rishavy
authors.forename: Kathleen L
authors.initials: KL
authors.lastname: Berkner
mesh_terms: D000818:Animals; D019735:Carbon-Carbon Ligases / Q000235:genetics / Q000378:metabolism*; D002384:Catalysis; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D010084:Oxidation-Reduction; D017293:Protein S / Q000378:metabolism*; D014812:Vitamin K / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017293:Protein S; D014812:Vitamin K; D018698:Glutamic Acid; D019735:Carbon-Carbon Ligases; C020660:glutamyl carboxylase