Abstract
Author SummaryThe biosynthesis of Vitamin K and Coenzyme Q requires the transfer of a long, hydrophobic moiety known as an isoprenyl onto an aromatic acceptor compound. This process is catalyzed by a family of proteins known as the UbiA proteins, which are embedded in the hydrophobic environment of cell membranes. To understand how the prenyltransfer reaction is carried out, we solved the three-dimensional structure of a member of the UbiA family by X-ray crystallography. This structure reveals how magnesium ions and the prenyl substrate are bound within a sealed amphipathic chamber inside the protein and suggests how the reaction intermediate may be stabilized by the protein and protected from the solvent. Functional studies carried out on another member of the UbiA family, as well as comparison to known disease-causing mutations in the human homolog UBIAD1, demonstrate that the residues involved in this process are conserved across the UbiA family.
Highlights
Vitamin K is an essential cofactor required for the posttranslational modification of proteins involved in blood-clotting and normal bone metabolism
The biosynthesis of Vitamin K and Coenzyme Q requires the transfer of a long, hydrophobic moiety known as an isoprenyl onto an aromatic acceptor compound
Proteins for suitability for crystallization, a homolog from the extremophile Archaeoglobus fulgidus (AfUbiA) was chosen for further study based on its stability in detergent (Figure S2A)
Summary
Vitamin K is an essential cofactor required for the posttranslational modification of proteins involved in blood-clotting and normal bone metabolism. One of the major forms of vitamin K in humans, menaquinone-4, is produced by cleaving the phytyl group from dietary phylloquinone to produce menadione, which is modified with a polyprenyl group donated from geranylgeranyl diphosphate (Figure S1). This latter step is catalyzed by the protein UBIAD1, a member of a family of integral membrane proteins known collectively as UbiA prenyltransferases [1,2,3]. A representative reaction, catalyzed by the eponymous E. coli protein UbiA, involves the cleavage of the C–O bond in polyprenyl diphosphates of variable length and transfer of the prenyl chain to the ortho position of the phenol 4-hydroxybenzoic acid (4HB; Figure 1A). UbiA family members are typically predicted to contain eight or nine transmembrane helices and have two characteristic conserved motifs with the consensus sequences NDXXDXXXD and DXXXD (Figure 1B), often referred to as the first and second aspartate-rich motifs, respectively
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