From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma

Lykins, Joseph and Moschitto, Mathew J. and Zhou, Ying and Filippova, Ekaterina V. and Le, Hoang V. and Tomita, Tadakimi and Fox, Barbara A. and Bzik, David J. and Su, Chunlei and Rajagopala, Seesandra V. and Flores, Kristin and Spano, Furio and Woods, Stuart and Roberts, Craig W. and Hua, Cong and El Bissati, Kamal and Wheeler, Kelsey M. and Dovgin, Sarah and Muench, Stephen P. and McPhillie, Martin and Fishwick, Colin W.G. and Anderson, Wayne F. and Lee, Patricia J. and Hickman, Mark and Weiss, Louis M. and Dubey, Jitender P. and Lorenzi, Hernan A. and Silverman, Richard B. and McLeod, Rima L. (2024) From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma. iScience, 27 (1). 108477. ISSN 2589-0042 (https://doi.org/10.1016/j.isci.2023.108477)

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Abstract

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 1.55 Å 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. Increased sporozoite/merozoite TgO/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 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.

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