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

Joseph Lykins; Matthew J. Moschitto; Ying Zhou; Ekaterina V. Filippova; Hoang V. Le; Tadakimi Tomita; Barbara A. Fox; David J. Bzik; Chunlei Su; Seesandra V. Rajagopala; Kristin Flores; Furio Spano; Stuart Woods; Craig W. Roberts; Cong Hua; Kamal El Bissati; Kelsey M. Wheeler; Sarah Dovgin; Stephen P. Muench; Martin McPhillie; Colin W.G. Fishwick; Wayne F. Anderson; Patricia J. Lee; Mark Hickman; Louis M. Weiss; Jitender P. Dubey; Hernan A. Lorenzi; Richard B. Silverman; Rima L. McLeod

doi:10.1016/j.isci.2023.108477

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

Joseph Lykins, Matthew J. Moschitto, Ying Zhou, Ekaterina V. Filippova^*, Hoang V. Le, Tadakimi Tomita, Barbara A. Fox, David J. Bzik, Chunlei Su, Seesandra V. Rajagopala, Kristin Flores, Furio Spano, Stuart Woods, Craig W. Roberts, Cong Hua, Kamal El Bissati, Kelsey M. Wheeler, Sarah Dovgin, Stephen P. Muench, Martin McPhillieColin W.G. Fishwick, Wayne F. Anderson, Patricia J. Lee, Mark Hickman, Louis M. Weiss, Jitender P. Dubey, Hernan A. Lorenzi, Richard B. Silverman, Rima L. McLeod

^*Corresponding author for this work

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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.

Original language	English
Article number	108477
Number of pages	54
Journal	iScience
Volume	27
Issue number	1
Early online date	15 Nov 2023
DOIs	https://doi.org/10.1016/j.isci.2023.108477
Publication status	Published - 19 Jan 2024
Externally published	Yes

Keywords

parasitology
cell biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.isci.2023.108477Licence: CC BY-NC-ND

2023 11 13 Lykins et al Toxoplasma finalFinal published version, 13.5 MBLicence: CC BY-NC-ND

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Lykins, J., Moschitto, M. J., Zhou, Y., Filippova, E. V., Le, H. V., Tomita, T., Fox, B. A., Bzik, D. J., Su, C., Rajagopala, S. V., Flores, K., Spano, F., Woods, S., Roberts, C. W., Hua, C., Bissati, K. E., Wheeler, K. M., Dovgin, S., Muench, S. P., ... McLeod, R. L. (2024). From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma. iScience, 27(1), Article 108477. https://doi.org/10.1016/j.isci.2023.108477

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

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 {\AA} 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{\textquoteright}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{\textquoteright}s capacity to make gametes that fuse to become zygotes, thereby contaminating environments and causing disease.",

keywords = "parasitology, cell biology",

author = "Joseph Lykins and Moschitto, {Matthew J.} and Ying Zhou and Filippova, {Ekaterina V.} and Le, {Hoang V.} and Tadakimi Tomita and Fox, {Barbara A.} and Bzik, {David J.} and Chunlei Su and Rajagopala, {Seesandra V.} and Kristin Flores and Furio Spano and Stuart Woods and Roberts, {Craig W.} and Cong Hua and Bissati, {Kamal El} and Wheeler, {Kelsey M.} and Sarah Dovgin and Muench, {Stephen P.} and Martin McPhillie and Fishwick, {Colin W.G.} and Anderson, {Wayne F.} and Lee, {Patricia J.} and Mark Hickman and Weiss, {Louis M.} and Dubey, {Jitender P.} and Lorenzi, {Hernan A.} and Silverman, {Richard B.} and McLeod, {Rima L.}",

year = "2024",

month = jan,

day = "19",

doi = "10.1016/j.isci.2023.108477",

language = "English",

volume = "27",

journal = "iScience",

issn = "2589-0042",

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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, Bissati, KE, 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 2024, 'From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma', iScience, vol. 27, no. 1, 108477. https://doi.org/10.1016/j.isci.2023.108477

TY - JOUR

T1 - From TgO/GABA-AT, GABA, and T-263 mutant to conception of Toxoplasma

AU - Lykins, Joseph

AU - Moschitto, Matthew J.

AU - Zhou, Ying

AU - Filippova, Ekaterina V.

AU - Le, Hoang V.

AU - Tomita, Tadakimi

AU - Fox, Barbara A.

AU - Bzik, David J.

AU - Su, Chunlei

AU - Rajagopala, Seesandra V.

AU - Flores, Kristin

AU - Spano, Furio

AU - Woods, Stuart

AU - Roberts, Craig W.

AU - Hua, Cong

AU - Bissati, Kamal El

AU - Wheeler, Kelsey M.

AU - Dovgin, Sarah

AU - Muench, Stephen P.

AU - McPhillie, Martin

AU - Fishwick, Colin W.G.

AU - Anderson, Wayne F.

AU - Lee, Patricia J.

AU - Hickman, Mark

AU - Weiss, Louis M.

AU - Dubey, Jitender P.

AU - Lorenzi, Hernan A.

AU - Silverman, Richard B.

AU - McLeod, Rima L.

PY - 2024/1/19

Y1 - 2024/1/19

N2 - 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.

AB - 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.

KW - parasitology

KW - cell biology

UR - https://pureportal.strath.ac.uk/en/publications/15adb73b-b920-4742-9789-e4a438a6dc8d

U2 - 10.1016/j.isci.2023.108477

DO - 10.1016/j.isci.2023.108477

M3 - Article

SN - 2589-0042

VL - 27

JO - iScience

JF - iScience

IS - 1

M1 - 108477

ER -

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

Abstract

Keywords

UN SDGs

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