Bringing Bioactive Compounds into Membranes: The UbiA Superfamily of Intramembrane Aromatic Prenyltransferases

Abstract

The UbiA superfamily of intramembrane prenyltransferases catalyzes a key biosynthetic step in the production of ubiquinones, menaquinones, plastoquinones, hemes, chlorophylls, vitamin E, and structural lipids. These lipophilic 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. This article reviews the biological functions and enzymatic activities of representative members of the superfamily, focusing on the remarkable recent research progress revealing that the UbiA superfamily is centrally implicated in several important physiological processes and human diseases. Because prenyltransferases in this superfamily have distinctive substrate preferences, two recent crystal structures are compared to illuminate the general mechanism for substrate recognition.

The plastid genome of some eustigmatophyte algae harbours a bacteria-derived six-gene cluster for biosynthesis of a novel secondary metabolite

“…Most of the EboC protein length aligns to the UbiA family model in Pfam and vice versa , and no other additional conserved domain could be found in EboC proteins, indicating that they entirely correspond to UbiA homologues. UbiA, an enzyme (4-hydroxybenzoate polyprenyltransferase) involved in ubiquinone biosynthesis [67], is a prototype of a much broader group of proteins with a similar structure and biochemical function, recently denoted as the UbiA superfamily [50]. Members of this group are intramembrane proteins that catalyse attachment of (poly)prenyl chains or their derivatives to different substrates.…”

“…Therefore, we applied a sequence clustering method recently used for mapping the sequence space of the UbiA superfamily, yet without EboC proteins (see fig. 1 in [50]). Our analysis revealed that EboC proteins constitute a distinct sequence cluster within the UbiA superfamily (figure 6).…”

“…For EboC, the procedure followed a recently reported analysis of the UbiA superfamily [50], which did not consider EboC proteins. Representative members of previously defined UbiA superfamily subgroups (listed in [50]) were used as queries for blastp searches against the NCBI nr database filtered for 70% maximum sequence identity (nr70). Up to 100 best hits (satisfying the E-value threshold of 1 × 10 −5 ) were taken for each query.…”

Structural basis for catalysis at the membrane-water interface

“…These molecules play key roles in electron and proton transport and respiration, photosynthesis, lipid metabolism, cell signaling, and cell wall formation [59]. They can also act as antioxidants and cofactors [61].…”

“…For example, UBIAD1 transfers an isoprenyl chain from geranylgeranyl pyrophosphate to menadione phylloquinone yielding menaquinone-4 (the major storage form of vitamin K) important in mitochondria, while in the Golgi, it participates in the synthesis of ubiquinone UQ 10 by a similar mechanism. Exceptions to this observed substrate promiscuity exist within the family, such as PHB geranyltransferase from Lithospermum erythrorhizon, which can only utilize geranylpyrophosphate (GPP) as a prenyl donor [59]. The promiscuity or fidelity of enzymes of the same family for lipidic substrates presents an intriguing problem from a structural perspective.…”