A chemical biology approach to the study of Coenzyme Q biosynthesis and metabolism

Abstract

Coenzyme Q (ubiquinone or Q) is a redox active lipid molecule, with a fully substituted benzoquinone ring and a polyisoprenoid tail with variable number of isoprene units. Humans synthesize Q10 with ten isoprene units, while Saccharomyces cerevisiae synthesize Q6. In eukaryotic cells Q is an essential component of the mitochondrial respiratory electron transport chain and an essential antioxidant. Q deficiency has been linked to mitochondrial, cardiovascular, and neurodegenerative diseases. The pathway of Q biosynthesis has still not been completely characterized. Therefore, it is vital to have a deeper understanding of the biosynthesis and metabolism of Q, to properly address its effects on health. In this study, farnesylated analogs (containing 3 isoprene units) of several Q‐intermediates have been chemically synthesized. The synthesis of 2‐farnesyl‐1,4‐hydroquinone serves as an analog of 3‐hexaprenyl‐4‐hydroxyphenol, which accumulates in yeast coq6 and coq9 mutants that over‐express the Coq8 polypeptide. In addition farnesylated analogs of 5‐demethoxy‐Q3 (DMQ3), 2‐demethyl‐5‐demethoxy‐Q3 (DDMQ3), and 2‐demethyl‐5‐demethoxy‐4‐amino‐Q3 (IDDMQ3H2) were chemically synthesized. The farnesylated analogs are added to yeast cell cultures to determine whether they serve as precursors and/or intermediates in the biosynthesis of Q3. Also, other selected farnesylated substrates such as 3‐farnesyl‐4‐hydroxybenzoic acid, 3‐farnesyl‐4,5‐dihydroxybenzoic acid, and other derivatives, are being synthesized to study Q metabolism. These substrates can also serve as ligands in protein binding assays and as substrates with isolated enzymes. Polyphenolic substrates, such as resveratrol, and p‐coumarate act as ring precursors for Q production in both yeast and mammalian cells. Here we investigate a number of other selected polyphenolic compounds that include kaempferol, ferulic acid, vanillin, and curcumin, to analyze their role as possible ring precursors for Q biosynthesis, in yeast and mammalian cells. Thereby we hope to understand and further characterize the biosynthetic and metabolic pathways responsible for Q biosynthesis, and function in different living systems.Support or Funding InformationThis research was supported by NSF MCB‐1330803.