FIG. 4.

Proposed scheme for ubiquinone biosynthesis in P. carinii and the effects of atovaquone (Av). The precursors PHBA and geranyl P-P are formed in the cytosol. Elongation of the polyprenyl precursor by the addition of isopentenyl units may occur at the outer surface of the ER, and then heptaprenyl P-P is translocated to the ER and then to the Golgi apparatus lumen. At 10 nM atovaquone, the drug acts as an analog of CoQ₁₀ and inhibits the PHBA-polyprenyltransferase activity (−), reducing the incorporation of PHBA into CoQ. In this model, it is proposed that decreased respiration stimulates the upregulation of biosyntheses of components involved in the intracellular translocation of CoQ (e.g., carrier) and/or electron transport (e.g., ubiquinone), which can override (++) the negative, end product feedback control(s). With atovaquone at concentrations of >1 μM, respiration is sufficiently inhibited and the reduction in ATP production by oxidative phosphorylation becomes measureable. The lack of ATP causes a decline in overall cellular metabolism, resulting in a decrease (−) in the rate of PHBA incorporation into CoQ. Ca, carrier.