bims-toxgon 2023-01-22 papers

bims-toxgon

Biomed News

on Toxoplasma gondii metabolism

Issue of 2023–01–22
eight papers selected by
Lakesh Kumar, BITS Pilani

Acetyl-CoA metabolism in cancer.
Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii.
In-silico identification of Tyr232 in AMPKα2 as a dephosphorylation site for the protein tyrosine phosphatase PTP-PEST.
Toxoplasmosis Infection during Pregnancy.
Seroprevalence of Toxoplasma gondii in domestic cats, dogs and rabbits from Poland.
HAT- and HDAC-Targeted Protein Acetylation in the Occurrence and Treatment of Epilepsy.
Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.
SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis.

Nat Rev Cancer. 2023 Jan 19.

Acetyl-CoA metabolism in cancer.

David A Guertin, Kathryn E Wellen.

Few metabolites can claim a more central and versatile role in cell metabolism than acetyl coenzyme A (acetyl-CoA). Acetyl-CoA is produced during nutrient catabolism to fuel the tricarboxylic acid cycle and is the essential building block for fatty acid and isoprenoid biosynthesis. It also functions as a signalling metabolite as the substrate for lysine acetylation reactions, enabling the modulation of protein functions in response to acetyl-CoA availability. Recent years have seen exciting advances in our understanding of acetyl-CoA metabolism in normal physiology and in cancer, buoyed by new mouse models, in vivo stable-isotope tracing approaches and improved methods for measuring acetyl-CoA, including in specific subcellular compartments. Efforts to target acetyl-CoA metabolic enzymes are also advancing, with one therapeutic agent targeting acetyl-CoA synthesis receiving approval from the US Food and Drug Administration. In this Review, we give an overview of the regulation and cancer relevance of major metabolic pathways in which acetyl-CoA participates. We further discuss recent advances in understanding acetyl-CoA metabolism in normal tissues and tumours and the potential for targeting these pathways therapeutically. We conclude with a commentary on emerging nodes of acetyl-CoA metabolism that may impact cancer biology.

DOI: https://doi.org/10.1038/s41568-022-00543-5
ACS Infect Dis. 2023 Jan 18.

Structural Basis for Cyclosporin Isoform-Specific Inhibition of Cyclophilins from Toxoplasma gondii.

Filippo Favretto, Eva Jiménez-Faraco, Carolina Conter, Paola Dominici, Juan A Hermoso, Alessandra Astegno.

  Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. A possible mechanism of action involves CsA binding to T. gondii cyclophilins, although much remains to be understood. Herein, we characterize the functional and structural properties of a conserved (TgCyp23) and a more divergent (TgCyp18.4) cyclophilin isoform from T. gondii. While TgCyp23 is a highly active cis-trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at the atomic resolution showing the molecular details of CsA recognition by the protein. Computational and structural studies revealed relevant differences at the CsA-binding site between TgCyp18.4 and TgCyp23, suggesting that the two cyclophilins might have distinct functions in the parasite. These studies highlight the extensive diversification of TgCyps and pave the way for antiparasite interventions based on selective targeting of cyclophilins.

Keywords:  Toxoplasma gondii; chaperone-like activity; crystal structure; cyclophilin; cyclosporin; peptidyl-prolyl isomerization

DOI:  https://doi.org/10.1021/acsinfecdis.2c00566
Proteins. 2023 Jan 16.

In-silico identification of Tyr232 in AMPKα2 as a dephosphorylation site for the protein tyrosine phosphatase PTP-PEST.

Amrutha Manikandan, T S Sreevidya, Narayanan Manoj, Satyavani Vemparala, Madhulika Dixit.

  The AMP-activated protein kinase (AMPK) is known to be activated by the protein tyrosine phosphatase non-receptor type 12 (PTP-PEST) under hypoxic conditions. This activation is mediated by tyrosine dephosphorylation of the AMPKα subunit. However, the identity of the phosphotyrosine residues that PTP-PEST dephosphorylates remains unknown. In this study, we first predicted the structure of the complex of the AMPKα2 subunit and PTP-PEST catalytic domain using bioinformatics tools and further confirmed the stability of the complex using molecular dynamics simulations. Evaluation of the protein-protein interfaces indicated that residue Tyr232 is the most likely dephosphorylation site on AMPKα2. In addition, we explored the effect of phosphorylation of PTP-PEST residue Tyr64 on the stability of the complex. Phosphorylation of the highly conserved Tyr64, an interface residue, enhances the stability of the complex via the rearrangement of a network of electrostatic interactions in conjunction with conformational changes in the catalytic WPD loop. We generated a phosphomimetic (PTP-PEST-Y64D) mutant and used co-immunoprecipitation to study the effect of PTP-PEST phosphorylation on AMPKα2 binding. The mutant exhibited an increased affinity for AMPKα2 and corroborated the in-silico predictions. Together, our findings present a plausible structural basis of AMPK regulation by PTP-PEST and show how phosphorylation of PTP-PEST affects its interaction with AMPKα2. This article is protected by copyright. All rights reserved.

Keywords:  AMP-Activated Protein Kinase; Molecular docking analysis; Molecular dynamics simulation; Phosphorylation sites; Protein Tyrosine Phosphatase

DOI:  https://doi.org/10.1002/prot.26470
Trop Med Infect Dis. 2022 Dec 21. pii: 3. [Epub ahead of print]8(1):

Toxoplasmosis Infection during Pregnancy.

Myla Deganich, Crystal Boudreaux, Imaan Benmerzouga.

  This literature review aims to give an overview of the current knowledge concerning how a toxoplasmosis infection affects the mother and her fetus. A thorough search of PubMed and a complimentary search of Google Scholar databases were used to identify relevant studies for this review. Although a Toxoplasma gondii infection is preventable, this infection is contracted by consuming contaminated food and water and by exposure to environmental sources of infection such as contaminated soil. Maternal-to-fetal transmission of this infection can result in devastating ophthalmic and neurological consequences for the fetus. Although a toxoplasmosis infection can result in long-term effects on the fetus, chronic disease is also associated with mental illness in mothers. Effective treatment can reduce the risk of congenital toxoplasmosis and the long-term consequences of infection in the fetus. Without appropriate screening and education programs, this infection will remain largely undiagnosed.

Keywords:  Toxoplasma gondii; congenital toxoplasmosis; infection; pregnancy

DOI:  https://doi.org/10.3390/tropicalmed8010003
Vet Res Commun. 2023 Jan 16.

Seroprevalence of Toxoplasma gondii in domestic cats, dogs and rabbits from Poland.

Hanna Turlewicz-Podbielska, Jakub Jędrzej Ruszkowski, Maciej Gogulski, Małgorzata Pomorska-Mól.

  The seroprevalence of Toxoplasma gondii in domestic cats, dogs and rabbits was evaluated. Samples from cats and dogs were collected from five veterinary practices from various parts of Poland - Poznan (wielkopolskie voivodeship), Przemysl (podkarpackie voivodeship), Kluczbork (opolskie voivodeship), Lublin (lubelskie voivodeship) and Deblin (lubelskie voivodeship). Moreover, the samples from rabbits were collected in Poznan. In total, serum samples from 193 cats, 204 dogs and 71 rabbits were randomly selected and tested for specific antibodies against T. gondii using a commercial ELISA test. Pathogen seroprevalence among cats and dogs was calculated at a 95% confidence interval (CI) for each sex and age category (up to 12 months, 1-3 years, 4-7 years and over 8 years) and compared with a chi-squared test. The highest seroprevalence of T. gondii was noted in cats - 49.74% (96/193; 95% CI: 42.76-56.73). In dogs, it reached 28.92% (59/204; 95% CI: 23.13-35.49). Only 1 rabbit (3-year-old male) was seropositive, and the seroprevalence in rabbits was 1.41% (1/71; 95% CI: 0.25-7.56). A statistically significant correlation between seropositivity and age (p < 0.05) was observed in cats and dogs. No statistically significant difference in seroprevalence concerning gender or location was found in cats and dogs. Our findings indicate that cat and dog serum samples had a high frequency of anti-T. gondii antibodies, while rabbit serum samples had low frequency and that these species are exposed to T. gondii in Poland and develop humoral response due to infection.

Keywords:  Cats; Dogs; Rabbits; Seroprevalence; Toxoplasma gondii

DOI:  https://doi.org/10.1007/s11259-022-10055-0
Biomedicines. 2022 Dec 29. pii: 88. [Epub ahead of print]11(1):

HAT- and HDAC-Targeted Protein Acetylation in the Occurrence and Treatment of Epilepsy.

Jie Wang, Feng Yun, Jiahui Sui, Wenpeng Liang, Dingding Shen, Qi Zhang.

  Epilepsy is a common and severe chronic neurological disorder. Recently, post-translational modification (PTM) mechanisms, especially protein acetylation modifications, have been widely studied in various epilepsy models or patients. Acetylation is regulated by two classes of enzymes, histone acetyltransferases (HATs) and histone deacetylases (HDACs). HATs catalyze the transfer of the acetyl group to a lysine residue, while HDACs catalyze acetyl group removal. The expression of many genes related to epilepsy is regulated by histone acetylation and deacetylation. Moreover, the acetylation modification of some non-histone substrates is also associated with epilepsy. Various molecules have been developed as HDAC inhibitors (HDACi), which have become potential antiepileptic drugs for epilepsy treatment. In this review, we summarize the changes in acetylation modification in epileptogenesis and the applications of HDACi in the treatment of epilepsy as well as the mechanisms involved. As most of the published research has focused on the differential expression of proteins that are known to be acetylated and the knowledge of whole acetylome changes in epilepsy is still minimal, a further understanding of acetylation regulation will help us explore the pathological mechanism of epilepsy and provide novel ideas for treating epilepsy.

Keywords:  acetylation; deacetylation; epilepsy; histone acetyltransferases (HATs); histone deacetylase inhibitors (HDACi); histone deacetylases (HDACs)

DOI:  https://doi.org/10.3390/biomedicines11010088
Cancers (Basel). 2023 Jan 12. pii: 484. [Epub ahead of print]15(2):

Pyruvate Dehydrogenase Inhibition Leads to Decreased Glycolysis, Increased Reliance on Gluconeogenesis and Alternative Sources of Acetyl-CoA in Acute Myeloid Leukemia.

Rebecca Anderson, Kristin M Pladna, Nathaniel J Schramm, Frances B Wheeler, Steven Kridel, Timothy S Pardee.

  Acute myeloid leukemia (AML) is an aggressive disease characterized by poor outcomes and therapy resistance. Devimistat is a novel agent that inhibits pyruvate dehydrogenase complex (PDH). A phase III clinical trial in AML patients combining devimistat and chemotherapy was terminated for futility, suggesting AML cells were able to circumvent the metabolic inhibition of devimistat. The means by which AML cells resist PDH inhibition is unknown. AML cell lines treated with devimistat or deleted for the essential PDH subunit, PDHA, showed a decrease in glycolysis and decreased glucose uptake due to a reduction of the glucose transporter GLUT1 and hexokinase II. Both devimistat-treated and PDHA knockout cells displayed increased sensitivity to 2-deoxyglucose, demonstrating reliance on residual glycolysis. The rate limiting gluconeogenic enzyme phosphoenolpyruvate carboxykinase 2 (PCK2) was significantly upregulated in devimistat-treated cells, and its inhibition increased sensitivity to devimistat. The gluconeogenic amino acids glutamine and asparagine protected AML cells from devimistat. Non-glycolytic sources of acetyl-CoA were also important with fatty acid oxidation, ATP citrate lyase (ACLY) and acyl-CoA synthetase short chain family member 2 (ACSS2) contributing to resistance. Finally, devimistat reduced fatty acid synthase (FASN) activity. Taken together, this suggests that AML cells compensate for PDH and glycolysis inhibition by gluconeogenesis for maintenance of essential glycolytic intermediates and fatty acid oxidation, ACLY and ACSS2 for non-glycolytic production of acetyl-CoA. Strategies to target these escape pathways should be explored in AML.

Keywords:  leukemia; metabolism; mitochondria; therapy

DOI:  https://doi.org/10.3390/cancers15020484
Exp Mol Med. 2023 Jan 18.

SIRT5-related desuccinylation modification of AIFM1 protects against compression-induced intervertebral disc degeneration by regulating mitochondrial homeostasis.

Jianxin Mao, Di Wang, Dong Wang, Qi Wu, Qiliang Shang, Chu Gao, Huanbo Wang, Han Wang, Mu Du, Pandi Peng, Haoruo Jia, Xiaolong Xu, Jie Wang, Liu Yang, Zhuojing Luo.

Mitochondrial dysfunction plays a major role in the development of intervertebral disc degeneration (IDD). Sirtuin 5 (SIRT5) participates in the maintenance of mitochondrial homeostasis through its desuccinylase activity. However, it is still unclear whether succinylation or SIRT5 is involved in the impairment of mitochondria and development of IDD induced by excessive mechanical stress. Our 4D label-free quantitative proteomic results showed decreased expression of the desuccinylase SIRT5 in rat nucleus pulposus (NP) tissues under mechanical loading. Overexpression of Sirt5 effectively alleviated, whereas knockdown of Sirt5 aggravated, the apoptosis and dysfunction of NP cells under mechanical stress, consistent with the more severe IDD phenotype of Sirt5 KO mice than wild-type mice that underwent lumbar spine instability (LSI) surgery. Moreover, immunoprecipitation-coupled mass spectrometry (IP-MS) results suggested that AIFM1 was a downstream target of SIRT5, which was verified by a Co-IP assay. We further demonstrated that reduced SIRT5 expression resulted in the increased succinylation of AIFM1, which in turn abolished the interaction between AIFM1 and CHCHD4 and thus led to the reduced electron transfer chain (ETC) complex subunits in NP cells. Reduced ETC complex subunits resulted in mitochondrial dysfunction and the subsequent occurrence of IDD under mechanical stress. Finally, we validated the efficacy of treatments targeting disrupted mitochondrial protein importation by upregulating SIRT5 expression or methylene blue (MB) administration in the compression-induced rat IDD model. In conclusion, our study provides new insights into the occurrence and development of IDD and offers promising therapeutic approaches for IDD.

DOI: https://doi.org/10.1038/s12276-023-00928-y