Structure basis of biosynthesis of aromatic compounds in membranes
UBIAD1, the human synthetic enzyme of vitamin K, maintains vascular homeostasis by promoting endothelial cell survival, preventing oxidative damage in cardiovascular tissues, and sustaining mitochondrial function, while dysfunctional UBIAD1 has been linked to cardiovascular degeneration, Parkinson’s disease, Schnyder corneal dystrophy, and urologic cancers. UBIAD1 belongs to the UbiA superfamily of intramembrane prenyltransferases that generates the basic skeleton of quinones, hemes, chlorophylls, vitamin E, and special lipids. These important compounds serve as electron and proton carriers for cellular respiration and photosynthesis, as antioxidants to reduce cell damage, and as structural components of microbial cell walls and membranes. We have determined the structures of a UBIAD1 homolog. This is a significant achievement because intramembrane enzymes are highly underrepresented in the current knowledgebase. Only about 100 unique structures have been determined to date, among which we have determined the first VKOR structure and first structures in the UbiA superfamily. Our structure explained how aromatic compounds are prenylated to become soluble and functional in biological membranes, and revealed a new strategy by which intramembrane enzymes can achieve substrate access and catalyze reactions in a hydrophobic intramembrane setting. In unpublished work, we determined the structures of two DGGGPs, which synthesize the diether and tetraether lipids that constitute the unique archaeal membrane. Since structures of intramembrane enzymes are underrepresented in the current knowledgebase, our studies of these prenyltransferases make a particularly valuable contribution.
W. Cheng, W. Li, Science 343, 878-881 (2014)