Unique substrate specificity of ornithine aminotransferase from <i>Toxoplasma gondii</i>

Astegno, Alessandra; Maresi, Elena; Bertoldi, Mariarita; Verde, Valentina La; Paiardini, Alessandro; Dominici, Paola

doi:10.1042/bcj20161021

Cited by 19 publications

(17 citation statements)

References 53 publications

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“…value (~1.9 Å over 395 Cα atoms) is the structure of GABA-OAT from E. coli with sequence identity 31%. Recent reports indicate that Tg OAT shows a dual N-acetyl-ornithine (AcOrn) and γ-aminobutyric acid (GABA) transaminase activity and may function in both arginine and GABA metabolism (Astegno et al, 2017 ).…”

Section: Resultsmentioning

confidence: 99%

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

Lykins

Filippova

Halavaty

et al. 2018

Front. Cell. Infect. Microbiol.

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Toxoplasma gondii, an Apicomplexan parasite, causes significant morbidity and mortality, including severe disease in immunocompromised hosts and devastating congenital disease, with no effective treatment for the bradyzoite stage. To address this, we used the Tropical Disease Research database, crystallography, molecular modeling, and antisense to identify and characterize a range of potential therapeutic targets for toxoplasmosis. Phosphoglycerate mutase II (PGMII), nucleoside diphosphate kinase (NDK), ribulose phosphate 3-epimerase (RPE), ribose-5-phosphate isomerase (RPI), and ornithine aminotransferase (OAT) were structurally characterized. Crystallography revealed insights into the overall structure, protein oligomeric states and molecular details of active sites important for ligand recognition. Literature and molecular modeling suggested potential inhibitors and druggability. The targets were further studied with vivoPMO to interrupt enzyme synthesis, identifying the targets as potentially important to parasitic replication and, therefore, of therapeutic interest. Targeted vivoPMO resulted in statistically significant perturbation of parasite replication without concomitant host cell toxicity, consistent with a previous CRISPR/Cas9 screen showing PGM, RPE, and RPI contribute to parasite fitness. PGM, RPE, and RPI have the greatest promise for affecting replication in tachyzoites. These targets are shared between other medically important parasites and may have wider therapeutic potential.

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Section: Resultsmentioning

confidence: 99%

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

Lykins

Filippova

Halavaty

et al. 2018

Front. Cell. Infect. Microbiol.

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“…The yield was ~ 50 mg of protein/liter of cell culture. The cofactor (PLP) content was measured by treating TgCBS with 0.1 M NaOH and monitoring absorbance at 388 nm (ɛ 388 = 6,600 M −1 cm −1 ) 45,46 .…”

Section: Discussionmentioning

confidence: 99%

Cystathionine β-synthase is involved in cysteine biosynthesis and H2S generation in Toxoplasma gondii

Conter

Fruncillo

Fernández-Rodríguez

et al. 2020

Sci Rep

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Cystathionine β-synthase (CBS) catalyzes the condensation of serine and homocysteine to water and cystathionine, which is then hydrolyzed to cysteine, α-ketobutyrate and ammonia by cystathionine γ-lyase (CGL) in the reverse transsulfuration pathway. The protozoan parasite Toxoplasma gondii, the causative agent of toxoplasmosis, includes both CBS and CGL enzymes. We have recently reported that the putative T. gondii CGL gene encodes a functional enzyme. Herein, we cloned and biochemically characterized cDNA encoding CBS from T. gondii (TgCBS), which represents a first example of protozoan CBS that does not bind heme but possesses two C-terminal CBS domains. We demonstrated that TgCBS can use both serine and O-acetylserine to produce cystathionine, converting these substrates to an aminoacrylate intermediate as part of a PLP-catalyzed β-replacement reaction. Besides a role in cysteine biosynthesis, TgCBS can also efficiently produce hydrogen sulfide, preferentially via condensation of cysteine and homocysteine. Unlike the human counterpart and similar to CBS enzymes from lower organisms, the TgCBS activity is not stimulated by S-adenosylmethionine. This study establishes the presence of an intact functional reverse transsulfuration pathway in T. gondii and demonstrates the crucial role of TgCBS in biogenesis of H 2 S.

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“…We suspected that it would likely regulate the interaction between epithelial cells and the extracellular matrix leading to tissue destruction during T. gallinae invasion ( 46 ). Metabolic pathways and biosynthesis of antibiotics may also be associated with T. gallinae infections probably due to the function of genes like UGP2 and OAT that were reported to play a role in nematodes infection ( 47 ) and inhibiting Toxoplasma gondii ( 48 ).…”

Section: Discussionmentioning

confidence: 99%

Transcriptome Analysis Revealed Potential Mechanisms of Resistance to Trichomoniasis gallinae Infection in Pigeon (Columba livia)

Yuan¹,

Ni²,

Li³

et al. 2021

Front. Vet. Sci.

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Trichomoniasis gallinae (T. gallinae) is one of the most pathogenic parasites in pigeon, particularly in squabs. Oral cavity is the main site for the host-parasite interaction. Herein, we used RNA-sequencing technology to characterize lncRNA and mRNA profiles and compared transcriptomic dynamics of squabs, including four susceptible birds (S) from infected group, four tolerant birds (T) without parasites after T. gallinae infection, and three birds from uninfected group (N), to understand molecular mechanisms underlying host resistance to this parasite. We identified 29,809 putative lncRNAs and characterized their genomic features subsequently. Differentially expressed (DE) genes, DE-lncRNAs and cis/trans target genes of DE-lncRNAs were further compared among the three groups. The KEGG analysis indicated that specific intergroup DEGs were involved in carbon metabolism (S vs. T), metabolic pathways (N vs. T) and focal adhesion pathway (N vs. S), respectively. Whereas, the cis/trans genes of DE-lncRNAs were enriched in cytokine-cytokine receptor interaction, toll-like receptor signaling pathway, p53 signaling pathway and insulin signaling pathway, which play crucial roles in immune system of the host animal. This suggests T. gallinae invasion in pigeon mouth may modulate lncRNAs expression and their target genes. Moreover, co-expression analysis identified crucial lncRNA-mRNA interaction networks. Several DE-lncRNAs including MSTRG.82272.3, MSTRG.114849.42, MSTRG.39405.36, MSTRG.3338.5, and MSTRG.105872.2 targeted methylation and immune-related genes, such as JCHAIN, IL18BP, ANGPT1, TMRT10C, SAMD9L, and SOCS3. This implied that DE-lncRNAs exert critical influence on T. gallinae infections. The quantitative exploration of host transcriptome changes induced by T. gallinae infection broaden both transcriptomic and epigenetic insights into T. gallinae resistance and its pathological mechanism.

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Unique substrate specificity of ornithine aminotransferase from Toxoplasma gondii

Cited by 19 publications

References 53 publications

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

CSGID Solves Structures and Identifies Phenotypes for Five Enzymes in Toxoplasma gondii

Cystathionine β-synthase is involved in cysteine biosynthesis and H2S generation in Toxoplasma gondii

Transcriptome Analysis Revealed Potential Mechanisms of Resistance to Trichomoniasis gallinae Infection in Pigeon (Columba livia)

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