Lykins Joseph, Moschitto Matthew J, Zhou Ying, Filippova Ekaterina V, Le Hoang V, Tomita Tadakimi, Fox Barbara A, Bzik David J, Su Chunlei, Rajagopala Seesandra V, Flores Kristin, Spano Furio, Woods Stuart, Roberts Craig W, Hua Cong, El Bissati Kamal, Wheeler Kelsey M, Dovgin Sarah, Muench Stephen P, McPhillie Martin, Fishwick Colin W G, Anderson Wayne F, Lee Patricia J, Hickman Mark, Weiss Louis M, Dubey Jitender P, Lorenzi Hernan A, Silverman Richard B, McLeod Rima L
Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA.
Department of Chemistry, Department of Molecular Biosciences, Chemistry of Life Processes Institute, Center for Molecular Innovation and Drug Discovery, and Center for Developmental Therapeutics, Northwestern University, Evanston, IL 60208-3113, USA.
iScience. 2023 Nov 16;27(1):108477. doi: 10.1016/j.isci.2023.108477. eCollection 2024 Jan 19.
causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find ornithine aminotransferase (OAT) is conserved across phyla. We solve O/GABA-AT structures with bound inactivators at 1.55 Å and identify an inactivator selective for O/GABA-AT over human OAT and GABA-AT. However, abrogating O/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat's oocyst shedding. Increased sporozoite/merozoite O/GABA-AT expression led to our study of a mutagenized clone with oocyst formation blocked, arresting after forming male and female gametes, with "Rosetta stone"-like mutations in genes expressed in merozoites. Mutations are similar to those in organisms from plants to mammals, causing defects in conception and zygote formation, affecting merozoite capacitation, pH/ionicity/sodium-GABA concentrations, drawing attention to cyclic AMP/PKA, and genes enhancing energy or substrate formation in O/GABA-AT-related-pathways. These candidates potentially influence merozoite's capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease.
会引发发病和死亡，并通过猫的有性阶段广泛传播。在此，我们发现鸟氨酸转氨酶（OAT）在各门类中具有保守性。我们解析了与结合失活剂结合的O/GABA-AT结构，分辨率为1.55 Å，并鉴定出一种对O/GABA-AT具有选择性的失活剂，其对人OAT和GABA-AT的选择性更高。然而，通过基因敲除O/GABA-AT并不会减少寄生虫的复制、毒力、包囊形成，也无法消除猫的卵囊排出。子孢子/裂殖子O/GABA-AT表达的增加促使我们研究一个卵囊形成受阻的诱变克隆，该克隆在形成雄配子和雌配子后停滞，在裂殖子中表达的基因存在类似“罗塞塔石碑”的突变。这些突变与从植物到哺乳动物的生物体中的突变相似，会导致受精和受精卵形成缺陷，影响裂殖子获能、pH/离子性/钠-γ-氨基丁酸浓度，还会引起对环磷酸腺苷/蛋白激酶A以及在O/GABA-AT相关途径中增强能量或底物形成的基因的关注。这些候选因素可能会影响裂殖子产生融合形成受精卵的配子的能力，从而污染环境并引发疾病。
