Publications

From TgO/GABA-AT, GABA, and T-263 Mutant to Conception of Toxoplasma

Lykins J, Moschitto MJ, Zhou Y, Filippova EV, Le HV, Tomita T, Fox BA, Bzik DJ, Su C, Rajagopala SV, Flores K, Spano F, Woods S, Roberts CW, Hua C, El Bissati K, Wheeler KM, Dovgin S, Muench SP, McPhillie M, Fishwick CWG, Anderson WF, Lee PJ, Hickman M, Weiss LM, Dubey JP, Lorenzi HA, Silverman RB, McLeod RL

PMID: 38205261

Abstract

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.