Prenyldiphosphate synthases catalyze the reaction of allylic
diphosphates with one or more
isopentenyl diphosphate molecules to form compounds such as
farnesyl diphosphate, used in, e.g.,
sterol biosynthesis and protein prenylation, as well as longer "polyprenyl"
diphosphates, used in
ubiquinone and
menaquinone biosynthesis.
Quinones play an essential role in electron transport and are associated with the inner mitochondrial membrane due to the presence of the polyprenyl group. In this work, we investigated the synthesis of the polyprenyl
diphosphate that alkylates the
ubiquinone ring precursor in Toxoplasma gondii, an opportunistic pathogen that causes serious disease in immunocompromised patients and the unborn fetus. The
enzyme that catalyzes this early step of the
ubiquinone synthesis is
Coq1 (TgCoq1), and we show that it produces the C35 species heptaprenyl
diphosphate. TgCoq1 localizes to the mitochondrion and is essential for in vitro T. gondii growth. We demonstrate that the growth defect of a T. gondii TgCoq1 mutant is rescued by complementation with a homologous TgCoq1 gene or with a (C45)
solanesyl diphosphate synthase from Trypanosoma cruzi (TcSPPS). We find that a lipophilic
bisphosphonate (BPH-1218) inhibits T. gondii growth at low-nanomolar concentrations, while overexpression of the TgCoq1
enzyme dramatically reduced growth inhibition by the
bisphosphonate. Both the severe growth defect of the mutant and the inhibition by BPH-1218 were rescued by supplementation with a long-chain (C30)
ubiquinone (UQ6). Importantly, BPH-1218 also protected mice against a lethal T. gondii
infection. TgCoq1 thus represents a potential
drug target that could be exploited for improved
chemotherapy of
toxoplasmosis. IMPORTANCE Millions of people are infected with Toxoplasma gondii, and the available treatment for
toxoplasmosis is not ideal. Most of the drugs currently used are only effective for the acute
infection, and treatment can trigger serious side effects requiring changes in the therapeutic approach. There is, therefore, a compelling need for safe and effective treatments for
toxoplasmosis. In this work, we characterize an
enzyme of the mitochondrion of T. gondii that can be inhibited by an
isoprenoid pathway inhibitor. We present evidence that demonstrates that inhibition of the
enzyme is linked to parasite death. In addition, the inhibitor can protect mice against a lethal dose of T. gondii. Our results thus reveal a promising chemotherapeutic target for the development of new medicines for
toxoplasmosis.