iScience (Jan 2024)
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
Affiliations
- Joseph Lykins
- Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, USA
- Matthew J. Moschitto
- 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
- Ying Zhou
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA
- Ekaterina V. Filippova
- Center for Structural Genomics of Infectious Diseases and the Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Corresponding author
- Hoang V. Le
- 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
- Tadakimi Tomita
- Division of Parasitology, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Barbara A. Fox
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
- David J. Bzik
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
- Chunlei Su
- Department of Microbiology, University of Tennessee, Knoxville, TN 37996, USA
- Seesandra V. Rajagopala
- Department of Infectious Diseases, The J. Craig Venter Institute, 9704 Medical Center Drive, Rockville, MD 20850, USA
- Kristin Flores
- Center for Structural Genomics of Infectious Diseases and the Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA
- Furio Spano
- Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy
- Stuart Woods
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow Scotland, UK
- Craig W. Roberts
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow Scotland, UK
- Cong Hua
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA
- Kamal El Bissati
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA
- Kelsey M. Wheeler
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA
- Sarah Dovgin
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA
- Stephen P. Muench
- School of Biomedical Sciences and Astbury Centre for Structural Molecular Biology, The University of Leeds, Leeds, West York LS2 9JT, UK
- Martin McPhillie
- School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
- Colin W.G. Fishwick
- School of Chemistry and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, UK
- Wayne F. Anderson
- Center for Structural Genomics of Infectious Diseases and the Department of Biochemistry and Molecular Genetics, Northwestern University, Feinberg School of Medicine, Chicago, IL 60611, USA; Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA
- Patricia J. Lee
- Division of Experimental Therapeutics, Military Malaria Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA
- Mark Hickman
- Division of Experimental Therapeutics, Military Malaria Research Program, Walter Reed Army Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA
- Louis M. Weiss
- Division of Parasitology, Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Division of Infectious Diseases, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA
- Jitender P. Dubey
- Animal Parasitic Diseases Laboratory, Beltsville Agricultural Research Center, Agricultural Research Service, United States Department of Agriculture, Beltsville, MD 20705, USA
- Hernan A. Lorenzi
- Department of Infectious Diseases, The J. Craig Venter Institute, 9704 Medical Center Drive, Rockville, MD 20850, USA; Corresponding author
- Richard B. Silverman
- 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; Department of Pharmacology, Northwestern University, Chicago, IL 60611, USA; Corresponding author
- Rima L. McLeod
- Department of Ophthalmology and Visual Sciences, The University of Chicago, Chicago, IL 60637, USA; Department of Pediatrics (Infectious Diseases), Institute of Genomics, Genetics, and Systems Biology, Global Health Center, Toxoplasmosis Center, CHeSS, The College, University of Chicago, Chicago, IL 60637, USA; Corresponding author
- Journal volume & issue
-
Vol. 27,
no. 1
p. 108477
Abstract
Summary: 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.
