Professor Rima McLeod (Chicago, IL / US), Dr. Joseph Lykins (Chicago, IL / US), Professor Matthew Moschitto (Evanston, IL / US), Dr. Ying Zhou (Chicago, IL / US), Dr. Ekaterina Fillipova (Chicago, IL / US), Dr. Hoang V. Le (Bethesda, MD / US; Evanston, IL / US), Dr. Tadikimi Tomita (Bronx, NY / US), Dr. Barbara Fox (Hanover, NH / US), Professor David J Bzik (Hanover, NH / US), Professor Chunlei Su (Knoxville, TN / US), Dr. Seesandra V. Rajagopala Rajagopala (Rockville, MD / US), Kristin Flores (Chicago, IL / US), Professor Furio Spano (Rome / IT), Professor Stuart Woods (Glasgow / GB), Professor Craig W. Roberts (Glasgow / GB), Professor Cong Hua (Chicago, IL / US), Dr. Kelsey Wheeler (Chicago, IL / US), Dr. Kamal El Bissati (Chicago, IL / US), Sarah Dovgin (Chicago, IL / US), Professor Stephen P. Muench (Leeds / GB), Professor Martin McPhillie (Leeds / GB), Professor Colin W.G. Fishwick (Leeds / GB), Professor Wayne F. Anderson (Chicago, IL / US), Patricia J. Lee (Silver Spring, MD / US), Dr. Mark Hickman (Silver Spring, MD / US), Professor Louis M. Weiss (Bronx, NY / US), Dr. Jitender P. Dubey (Rockville, MD / US), Dr. Hernan A. Lorenzi (Rockville, MD / US), Professor Richard B. Silverman (Evanston, IL / US)
Toxoplasma gondii causes morbidity, mortality, and disseminates widely via cat sexual stages. Here, we find T. gondii ornithine aminotransferase (OAT) is conserved across phyla. We solve TgO/GABA-AT structures with bound inactivators at 1.55A°and identify an inactivator selective for TgO/GABA-AT over human OAT and GABA-AT. However, abrogating TgO/GABA-AT genetically does not diminish replication, virulence, cyst-formation, or eliminate cat"s oocyst shedding. Increasedsporozoite/merozoite TgO/GABAAT 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 TgO/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.
Origonally published in iScience 27, 108477, January 19, 2024 ª 2023 The Authors.