The Heptaprenyl Diphosphate Synthase (Coq1) Is the Target of a Lipophilic Bisphosphonate That Protects Mice against Toxoplasma gondii Infection.
The Heptaprenyl Diphosphate Synthase (Coq1) Is the Target of a Lipophilic Bisphosphonate That Protects Mice against Toxoplasma gondii Infection.
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DOI：
10.1128/mbio.01966-22
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发表时间：
2022-10-26
期刊：
影响因子：
6.4
通讯作者：
Moreno, Silvia N. J.
中科院分区：
文献类型：
--
作者：
Sleda, Melissa A.;Li, Zhu-Hong;Behera, Ranjan;Baierna, Baihetiya;Li, Catherine;Jumpathong, Jomkwan;Malwal, Satish R.;Kawamukai, Makoto;Oldfield, Eric;Moreno, Silvia N. J.
异戊二烯基二磷酸合酶催化烯丙基二磷酸与一个或多个异戊烯基二磷酸分子的反应，形成化合物，例如法尼基二磷酸，用于例如甾醇生物合成和蛋白质异戊二烯化，以及较长的“聚异戊二烯基”二磷酸，用于泛醌和甲基萘醌生物合成。醌在电子传递中起着重要作用，并且由于聚异戊二烯基团的存在而与线粒体内膜相关。在这项工作中，我们研究了聚异戊二烯二磷酸酯的合成，该聚异戊二烯基二磷酸酯可烷基化弓形虫中的泛醌环前体，弓形虫是一种机会性病原体，可导致免疫功能低下患者和未出生胎儿的严重疾病。催化泛醌合成这一早期步骤的酶是 Coq1 (TgCoq1)，我们表明它产生 C35 物种庚烯基二磷酸。 TgCoq1 定位于线粒体，对于体外弓形虫生长至关重要。我们证明，弓形虫 TgCoq1 突变体的生长缺陷可以通过与同源 TgCoq1 基因或来自克氏锥虫 (TcSPPS) 的 (C45) 茄尼基二磷酸合酶 (TcSPPS) 互补来挽救。我们发现亲脂性双膦酸盐 (BPH-1218) 在低纳摩尔浓度下抑制弓形虫生长，而 TgCoq1 酶的过度表达显着降低了双膦酸盐的生长抑制。通过补充长链 (C30) 泛醌 (UQ6) 可以挽救突变体的严重生长缺陷和 BPH-1218 的抑制。重要的是，BPH-1218 还可以保护小鼠免受致命的弓形虫感染。因此，TgCoq1 代表了一个潜在的药物靶点，可用于改善弓形体病的化疗。
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.
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DOI：
10.1093/bioinformatics/8.3.275
发表时间：
1992-06-01
期刊：
COMPUTER APPLICATIONS IN THE BIOSCIENCES
影响因子：
--
作者：
JONES, DT;TAYLOR, WR;THORNTON, JM
通讯作者：
THORNTON, JM
弓形虫病发育中的药物：进步，挑战和当前状态。
DOI：
10.2147/dddt.s60973
发表时间：
2017
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Alday PH;Doggett JS
通讯作者：
Doggett JS
影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
5.2
作者：
Imlay, Leah;Odom, Audrey R
通讯作者：
Odom, Audrey R
影响因子：
14.8
作者：
Kelley LA;Mezulis S;Yates CM;Wass MN;Sternberg MJ
通讯作者：
Sternberg MJ