The binding modes of quinones in flavoprotein oxidoreductases

Flavoprotein quinone reductases regenerate quinols which serve metabolic and antioxidant roles. These enzymes catalyze the two-electron oxidation of substrates and the subsequent two electron reduction of quinones. Despite the net two electron transfer between substrates, the binding mode of quinones is typically end-on to the flavin, rather than stacked, dictating that the oxidative half reaction cannot proceed via hydride transfer and must instead occur by two successive single electron transfers. Here we present a review of six of the most well-studied flavoprotein quinone reductases to establish a framework for discussing this positional orientation for the quinone oxidant. There are two non-mutually exclusive rationalizations for this binding mode where the flavin isoalloxazine acts as a redox partition. The first is that energetics of the single electron transfer pathway create a kinetic barrier to the reverse reaction, trapping electrons in the quinone pool and countering the high ratio of quinol to quinone present in the membrane. The second is that the end-on binding allows the enzymes to utilize different binding sites for cytosolic and membrane associated substrates, avoiding the need to desorb substrates. These effects may be additive and serve to funnel electrons into the quinone pool as efficiently as possible.