## 4 Specific Prenylquinones
### Ulbiquinone
#### 4.1.2 Ubiquinone in Parasitic Protozoa
Different homologs could be formed due to the promiscuity of UbiA for differently sized isoprenic chains or by a step-by-step UQ lateral chain formation process that has been previously suggested to occur in the fungus _Pneumocystis carini_. The fungus may produce UQ-10 from UQ-7 by repetitively adding 5-carbon isoprenic moieties to the lateral chain [158; 159], so UQ-7,8,9 can be considered intermediates for UQ-10 biosynthesis. This UQ biosynthetic pathway malaria parasites has been already investigated by confirming [14C] 4-hidroxyphenylzoate and radiolabeled isoprenic moietiesincorporation into UQ [54; 140]. However, pABA could also be an alternative UQ aromatic precursor in apicomplexan parasites since most of them form pABA for folate biosynthesis [149]. Furthermore, for both pABA and 4-hydroxybenzoate in _Plasmodium gallinaceum_, in vivo experiments in chicks suggested that exogenous incorporation from the host is essential for intraerythrocytic stages [149]. The good therapeutic effects and antiparasitic activities of hydroxynaphthaquinones have been previously demonstrated [160]. The best known compound among this class of compounds is atovaquone (2-[-trans-4-(chlorophenyl)-cyclohexyll-3-hydroxy-1,4-naphthquinone]), an antiparasitic agent that is specifically used to treat malaria, toxoplasmosis, babesiosis and pneumocystis pneumonia [161; 162]. The drug binds to the UQH\({}_{2}\)-binding site in the _bc1_ complex of several parasites with high affinity compared to mammalian mitochondria [135; 163], preventing mitochondrial ATP synthesis and maintaining a UQ pool [164]. In the treatment of malaria, the effects of atovaquone on parasite viability are not caused by a decrease in ATP synthesis. In _Plasmodium_, the lethal effects seem to be depletion of the UQ required for the activity of the enzyme dihydrorotate dehydrogenase (DHODH), which is necessary for pyrimidine biosynthesis [135; 165]. In clinics, atovaquone efficacy is improved by combination with proguanil, a folate biosynthesis inhibitor. Proguanil is a prodrug that is metabolized to cycloguanil, which in turn inhibits the enzyme dihydrofolateoreductase (DHFR) [166]. However, the synergic mechanism seems to be independent of DHFR inhibition [165; 167]. Furthermore, proguanil (but not cycloguanil) has been demonstrated to increase the ability of atovaquone to collapse the mitochondrial membrane potential (\(\Delta\Psi\) m) via a poorly understood mechanism [165; 167]. Unfortunately, in apicomplexan and trypanosomatid parasites, atovaquone resistance has been previously reported, even with pharmaceutical combinations containing other antiparasitic drugs [168; 169; 170]. In _P. falciparum_ and _T. gondii_, this resistance is thought to be caused by mutations in the mitochondrial complex III UQ-binding site [168; 169], while in _Leishmania infantum_ promastigotes, some studies linked the phenomenon with changes in the membrane lipidic composition [170]. Considering that UQ analogs that are less apolar than atovaquone can rescue the toxic effects of atovaquone in _Plasmodium_ and the parasitic ability to easily modify UQ biosynthesis [171], it would be interesting to also explore UQ biosynthesis as a mechanism involved in atovaquone resistance. It still has not been studied whether atovaquone resistance could involve UQ biosynthesis or the proportion between the different homologs. The only studies that have focused on the effects of atovaquone on UQ biosynthesis were performed in the fungus _Pneumocystis carinii_, which demonstrated that atovaquone inhibits UQ biosynthesis at 10 nM, exhibiting stimulation at 0.2 mM and inhibition again at 1 mM [158]. These surprising phenomena could be associated with the previously proposed unconventional UQ biosynthetic pathway [158; 159]. The effects of atovaquone on UQ biosynthesis/redox state remain to be demonstrated in pathogenic protozoa.