bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2024–03–17
eight papers selected by
Lakesh Kumar, BITS Pilani
  1. Constitutive upregulation of transcription factors underlies permissive bradyzoite differentiation in a natural isolate of Toxoplasma gondii.
  2. Iron Stress Affects the Growth and Differentiation of Toxoplasma gondii.
  3. Bicyclic pyrrolidine inhibitors of Toxoplasma gondii phenylalanine t-RNA synthetase with antiparasitic potency in vitro and brain exposure.
  4. In Vitro Anti-Toxoplasma Activity of Extracts Obtained from Tabebuia rosea and Tabebuia chrysantha: The Role of β-Amyrin.
  5. Current Trends in Sirtuin Activator and Inhibitor Development.
  6. Unraveling the Role of AtSRT2 in Energy Metabolism, Stress Responses, and Gene Expression during Osmotic Stress in Arabidopsis thaliana.
  7. Correction: The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.
  8. Structure-function analyses reveal Arabidopsis thaliana HDA7 to be an inactive histone deacetylase.
  1. bioRxiv. 2024 Feb 28. pii: 2024.02.28.582596. [Epub ahead of print]
    Constitutive upregulation of transcription factors underlies permissive bradyzoite differentiation in a natural isolate of Toxoplasma gondii.
    Jing Xia, Yong Fu, Wanyi Huang, L David Sibley.
      Toxoplasma gondii bradyzoites play a critical role in pathology due to their long-term persistence in intermediate hosts and their potential to reactivate, resulting in severe diseases in immunocompromised individuals. Currently there is no effective treatment for eliminating bradyzoites. Hence, better in vitro models of T. gondii cyst development would facilitate identification of therapeutic targets for bradyzoites. Herein we characterized a natural isolate of T. gondii , called Tg68, which showed slower in vitro replication of tachyzoites, and permissive bradyzoite development under stress conditions in vitro . Transcriptional analysis revealed constitutive expression in Tg68 tachyzoites of the key regulators of bradyzoite development including BFD1 , BFD2 , and several AP2 factors. Consistent with this finding, Tg68 tachyzoites expressed high levels of bradyzoite-specific genes including BAG1 , ENO1 , and LDH2 . Moreover, after stress induced differentiation, Tg68 bradyzoites exhibited gene expression profiles of mature bradyzoites, even at early time points. These data suggest that Tg68 tachyzoites exist in a pre-bradyzoite stage primed to readily develop into mature bradyzoites under stress conditions in vitro . Tg68 presents a novel model for differentiation in vitro that will serve as a useful tool for investigation of bradyzoite biology and development of therapeutics.
    Significance: Toxoplasma gondii is a widespread protozoan that chronically infects ∼30% of the world's population. T. gondii can differentiate between the fast-growing life stage that causes acute infection and the slow-growing stage that persists in the host for extended periods of time. The slow-growing stage cannot be eliminated by the host immune response or currently known antiparasitic drugs. Studies on the slow-growing stage have been limited due to the limitations of in vivo experiments and the challenges of in vitro manipulation. Here, we characterize a natural isolate of T. gondii , which constitutively expresses factors that drive development and that is permissive to convert to the slow-growing stage under stress conditions in vitro . The strain presents a novel in vitro model for studying the chronic phase of toxoplasmosis and identifying new therapeutic treatments for chronic infections.
    DOI:  https://doi.org/10.1101/2024.02.28.582596
  2. Int J Mol Sci. 2024 Feb 21. pii: 2493. [Epub ahead of print]25(5):
    Iron Stress Affects the Growth and Differentiation of Toxoplasma gondii.
    Zhu Ying, Meng Yin, Zifu Zhu, Zheng Shang, Yanqun Pei, Jing Liu, Qun Liu.
      Iron is an indispensable nutrient for the survival of Toxoplasma gondii; however, excessive amounts can lead to toxicity. The parasite must overcome the host's "nutritional immunity" barrier and compete with the host for iron. Since T. gondii can infect most nucleated cells, it encounters increased iron stress during parasitism. This study assessed the impact of iron stress, encompassing both iron depletion and iron accumulation, on the growth of T. gondii. Iron accumulation disrupted the redox balance of T. gondii while enhancing the parasite's ability to adhere in high-iron environments. Conversely, iron depletion promoted the differentiation of tachyzoites into bradyzoites. Proteomic analysis further revealed proteins affected by iron depletion and identified the involvement of phosphotyrosyl phosphatase activator proteins in bradyzoite formation.
    Keywords:  Toxoplasma gondii; bradyzoite differentiation; iron accumulation; iron depletion
    DOI:  https://doi.org/10.3390/ijms25052493
  3. bioRxiv. 2024 Feb 28. pii: 2024.02.28.582607. [Epub ahead of print]
    Bicyclic pyrrolidine inhibitors of Toxoplasma gondii phenylalanine t-RNA synthetase with antiparasitic potency in vitro and brain exposure.
    Chloe C Ence, Taher Uddin, Julien Borrel, Payal Mittal, Han Xie, Jochen Zoller, Amit Sharma, Eamon Comer, Stuart L Schreiber, Bruno Melillo, L David Sibley, Arnab K Chatterjee.
      Previous studies have shown that bicyclic azetidines are potent and selective inhibitors of apicomplexan phenylalanine tRNA synthetase (PheRS), leading to parasite growth inhibition in vitro and in vivo , including in models of Toxoplasma infection. Despite these useful properties, additional optimization is required for the development of efficacious treatments of toxoplasmosis from this inhibitor series, in particular to achieve sufficient exposure in the brain. Here, we describe a series of PheRS inhibitors built on a new bicyclic pyrrolidine core scaffold designed to retain the exit-vector geometry of the isomeric bicyclic azetidine core scaffold while offering avenues to sample diverse chemical space. Relative to the parent series, bicyclic pyrrolidines retain reasonable potency and target selectivity for parasite PheRS vs. host. Further structure-activity relationship studies revealed that the introduction of aliphatic groups improved potency, ADME and PK properties, including brain exposure. The identification of this new scaffold provides potential opportunities to extend the analog series to further improve selectivity and potency and ultimately deliver a novel, efficacious treatment of toxoplasmosis.
    Lay abstract: The inhibition of protein synthesis in parasites has emerged as an attractive strategy to target parasitic diseases such as malaria, cryptosporidiosis, and toxoplasmosis. In this study, we report a new series of small molecules that inhibit the enzyme responsible for loading the amino acid phenylalanine onto its cognate tRNA in the parasite species Toxoplasma , directly upstream of protein synthesis. We show that small molecules in this new series inhibit Toxoplasma parasite growth at low concentrations, and that, orally administered to mice, these molecules achieve high concentrations in the brain, which hold promise for the treatment of forms of toxoplasmosis that result from parasitic brain infection.
    DOI:  https://doi.org/10.1101/2024.02.28.582607
  4. Molecules. 2024 Feb 20. pii: 920. [Epub ahead of print]29(5):
    In Vitro Anti-Toxoplasma Activity of Extracts Obtained from Tabebuia rosea and Tabebuia chrysantha: The Role of β-Amyrin.
    Maria Camila Cardona-Trujillo, Francisco Javier Jiménez-González, Luz Angela Veloza, Juan Carlos Sepúlveda-Arias.
      Toxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii that is highly prevalent worldwide. Although the infection is asymptomatic in immunocompetent individuals, it severely affects immunocompromised individuals, causing conditions such as encephalitis, myocarditis, or pneumonitis. The limited therapeutic efficacy of drugs currently used to treat toxoplasmosis has prompted the search for new therapeutic alternatives. The aim of this study was to determine the anti-Toxoplasma activity of extracts obtained from two species of the genus Tabebuia. Twenty-six extracts, 12 obtained from Tabebuia chrysantha and 14 from Tabebuia rosea, were evaluated by a colorimetric technique using the RH strain of T. gondii that expresses β-galactosidase. Additionally, the activity of the promising extracts and their active compounds was evaluated by flow cytometry. β-amyrin was isolated from the chloroform extract obtained from the leaves of T. rosea and displayed important anti-Toxoplasma activity. The results show that natural products are an important source of new molecules with considerable biological and/or pharmacological activity.
    Keywords:  Bignoniaceae; Tabebuia chrysantha; Tabebuia rosea; Toxoplasma gondii; anti-Toxoplasma activity; β-amyrin
    DOI:  https://doi.org/10.3390/molecules29050920
  5. Molecules. 2024 Mar 06. pii: 1185. [Epub ahead of print]29(5):
    Current Trends in Sirtuin Activator and Inhibitor Development.
    Karina L Bursch, Christopher J Goetz, Brian C Smith.
      Sirtuins are NAD+-dependent protein deacylases and key metabolic regulators, coupling the cellular energy state with selective lysine deacylation to regulate many downstream cellular processes. Humans encode seven sirtuin isoforms (Sirt1-7) with diverse subcellular localization and deacylase targets. Sirtuins are considered protective anti-aging proteins since increased sirtuin activity is canonically associated with lifespan extension and decreased activity with developing aging-related diseases. However, sirtuins can also assume detrimental cellular roles where increased activity contributes to pathophysiology. Modulation of sirtuin activity by activators and inhibitors thus holds substantial potential for defining the cellular roles of sirtuins in health and disease and developing therapeutics. Instead of being comprehensive, this review discusses the well-characterized sirtuin activators and inhibitors available to date, particularly those with demonstrated selectivity, potency, and cellular activity. This review also provides recommendations regarding the best-in-class sirtuin activators and inhibitors for practical research as sirtuin modulator discovery and refinement evolve.
    Keywords:  drug development; epigenetics; lysine deacylation; sirtuins
    DOI:  https://doi.org/10.3390/molecules29051185
  6. Plants (Basel). 2024 Mar 02. pii: 711. [Epub ahead of print]13(5):
    Unraveling the Role of AtSRT2 in Energy Metabolism, Stress Responses, and Gene Expression during Osmotic Stress in Arabidopsis thaliana.
    Alberto Obrecht, Manuel Paneque.
      Sirtuins participate in chromatin remodeling and gene expression regulation during stress responses. They are the only deacetylases that couple the cellular NAD+-dependent energy metabolism with transcriptional regulation. They catalyze the production of nicotinamide, inhibiting sirtuin 2 (SIR2) activity in vivo. The SIR2 homolog, AtSRT2, deacetylates non-histone proteins associated with mitochondrial energy metabolism. To date, AtSRT2 mechanisms during stress responses in Arabidopsis thaliana remain unclear. The transduction of mitochondrial metabolic signals links the energy status to transcriptional regulation, growth, and stress responses. These signals induce changes by regulating nuclear gene expression. The present study aimed to determine the role of SRT2 and its product nicotinamide in the development of A. thaliana and the expression of osmotic stress-response genes. Leaf development was greater in srt2+ plants than in the wild type, indicating that SET2 plays a role in energy metabolism. Treatment with polyethylene glycol activated and inhibited gene expression in srt2- and srt2+ lines, respectively. Therefore, we concluded that SRT2-stimulated plant growth and repressed signaling are associated with osmotic stress.
    Keywords:  Arabidopsis; NAD+, mannitol; PEG; Sir2; osmotic stress; sirtuin
    DOI:  https://doi.org/10.3390/plants13050711
  7. Life Sci Alliance. 2024 Jun;pii: e202402684. [Epub ahead of print]7(6):
    Correction: The pyruvate dehydrogenase complex regulates mitophagic trafficking and protein phosphorylation.
    Panagiota Kolitsida, Vladimir Nolic, Jianwen Zhou, Michael Stumpe, Natalie M Niemi, Jörn Dengjel, Hagai Abeliovich.
      
    DOI:  https://doi.org/10.26508/lsa.202402684
  8. Curr Res Struct Biol. 2024 ;7 100136
    Structure-function analyses reveal Arabidopsis thaliana HDA7 to be an inactive histone deacetylase.
    Ketul Saharan, Somanath Baral, Nausad Hossain Shaikh, Dileep Vasudevan.
      Histone deacetylases (HDACs), responsible for the removal of acetyl groups from histone tails, are important epigenetic factors. They play a critical role in the regulation of gene expression and are significant in the context of plant growth and development. The Rpd3/Hda1 family of HDACs is reported to regulate key biological processes in plants, such as stress response, seed, embryonic, and floral development. Here, we characterized Arabidopsis thaliana HDA7, a Class I, Rpd3/Hda1 family HDAC. SAXS and AUC results show that the recombinantly expressed and purified histone deacetylase domain of AtHDA7 exists as a monomer in solution. Further, the crystal structure showed AtHDA7 to fold into the typical α/β arginase fold, characteristic of Rpd3/Hda1 family HDACs. Sequence analysis revealed that the Asp and His residues of the catalytic 'XDXH' motif present in functional Rpd3/Hda1 family HDACs are mutated to Gly and Pro, respectively, in AtHDA7, suggesting that it might be catalytically inactive. The Asp and His residues are important for Zn2+-binding. Not surprisingly, the crystal structure did not have Zn2+ bound in the catalytic pocket, which is essential for the HDAC activity. Further, our in vitro activity assay revealed AtHDA7 to be inactive as an HDAC. A search in the sequence databases suggested that homologs of AtHDA7 are found exclusively in the Brassicaceae family to which Arabidopsis belongs. It is possible that HDA7 descended from HDA6 through whole genome duplication and triplication events during evolution, as suggested in a previous phylogenetic study.
    Keywords:  Analytical ultracentrifugation; Histone deacetylases; Small-angle X-ray scattering; X-ray crystallography
    DOI:  https://doi.org/10.1016/j.crstbi.2024.100136
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