bims-toxgon Biomed News
on Toxoplasma gondii metabolism
Issue of 2025–05–25
nineteen papers selected by
Lakesh Kumar, BITS Pilani
  1. MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.
  2. Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex.
  3. Toxoplasma calcium-dependent protein kinases 3 mediates M1 macrophage polarization by targeting host Arginase-1.
  4. Toxoplasma gondii C2 Domain Protein Deletion Mutant as a Promising Vaccine Against Toxoplasmosis in Mice.
  5. TcCARP3 modulates compartmentalized cAMP signals involved in osmoregulation, infection of mammalian cells, and colonization of the triatomine vector in the human pathogen Trypanosoma cruzi.
  6. Cell-based determination of HDAC10-mediated polyamine deacetylase activity.
  7. TR-FRET assay for profiling HDAC10 inhibitors and PROTACs.
  8. Dynamic metabolic regulation of histone modifications during the yeast metabolic cycle.
  9. PfPPM2 signalling regulates asexual division and sexual conversion of human malaria parasite Plasmodium falciparum.
  10. Sirtuin Expression in Age-Associated Hepatic Response to Burn Trauma: Translational and Clinical Insights From a Murine Model.
  11. SIRT4 Controls Acetyl-CoA Synthesis to Promote Stemness and Invasiveness of Hepatocellular Carcinoma through Deacetylating MCCC2.
  12. Energy metabolism in Trypanosoma cruzi: the validated and putative bioenergetic and carbon sources.
  13. Molecular mimicry between parasites and cancer: a novel approach for developing cancer vaccines and therapeutic antibodies.
  14. Metabolism in hematology: Technological advances open new perspectives on disease biology and treatment.
  15. An enzyme activation network reveals extensive regulatory crosstalk between metabolic pathways.
  16. MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer.
  17. Analysing protein complexes in plant science: insights and limitation with AlphaFold 3.
  18. Biochemical Impact of p300-Mediated Acetylation of Replication Protein A: Implications for DNA Metabolic Pathway Choice.
  19. Mechano-metabolism on the rise.
  1. J Biol Chem. 2025 May 19. pii: S0021-9258(25)02098-8. [Epub ahead of print] 110248
    MULTIPLE, REDUNDANT CARBOXYLIC ACID TRANSPORTERS SUPPORT MITOCHONDRIAL METABOLISM IN PLASMODIUM FALCIPARUM.
    Krithika Rajaram, Gabriel W Rangel, Justin T Munro, Sethu C Nair, Rubayet Elahi, Manuel Llinás, Sean T Prigge.
      The mitochondrion of the deadliest human malaria parasite, Plasmodium falciparum, is an essential source of cellular acetyl-CoA during the asexual blood-stage of the parasite life cycle. Blocking mitochondrial acetyl-CoA synthesis leads to a hypoacetylated proteome and parasite death. We previously determined that mitochondrial acetyl-CoA is primarily synthesized from glucose-derived pyruvate by α-ketoacid dehydrogenases. Here, we asked if inhibiting the import of glycolytic pyruvate across the mitochondrial inner membrane would affect acetyl-CoA production and, thus, could be a potential target for antimalarial drug development. We selected the two predicted mitochondrial pyruvate carrier proteins, PfMPC1 (PF3D7_1340800) and PfMPC2 (PF3D7_1470400), for genetic knockout and isotopic metabolite tracing via HPLC-MS metabolomic analysis. Surprisingly, we observed that asexual blood-stage parasites could survive the loss of either or both PfMPCs with only minor growth defects, despite a substantial reduction in the amount of glucose-derived isotopic labelling into acetyl-CoA. Furthermore, genetic deletion of two additional mitochondrial carboxylic acid transporters - DTC (PF3D7_0823900, di/tricarboxylic acid carrier) and YHM2 (PF3D7_1223800, a putative citrate/α-ketoglutarate carrier protein) - only mildly affected blood-stage replication, even in the context of PfMPC deficiency. Although we observed no added impact on the incorporation of glucose carbon into acetyl-CoA in these quadruple knockout mutants, we noted a large decrease in glutamine-derived label in tricarboxylic acid cycle metabolites, suggesting that DTC and YHM2 both import glutamine derivatives into the mitochondrion. Altogether, our results demonstrate that redundant routes are used to fuel the blood-stage malaria parasite mitochondrion with imported carbon from two major sources - glucose and glutamine.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110248
  2. Nat Struct Mol Biol. 2025 May 19.
    Structure, assembly and inhibition of the Toxoplasma gondii respiratory chain supercomplex.
    Andrew E MacLean, Shikha Shikha, Mariana Ferreira Silva, Max J Gramelspacher, Aaron Nilsen, Katherine M Liebman, Sovitj Pou, Rolf W Winter, Amit Meir, Michael K Riscoe, J Stone Doggett, Lilach Sheiner, Alexander Mühleip.
      The apicomplexan mitochondrial electron transport chain is essential for parasite survival and displays a divergent subunit composition. Here we report cryo-electron microscopy structures of an apicomplexan III2-IV supercomplex and of the drug target complex III2. The supercomplex structure reveals how clade-specific subunits form an apicomplexan-conserved III2-IV interface with a unique, kinked architecture, suggesting that supercomplexes evolved independently in different eukaryotic lineages. A knockout resulting in supercomplex disassembly challenges the proposed role of III2-IV in electron transfer efficiency as suggested for mammals. Nevertheless, knockout analysis indicates that III2-IV is critical for parasite fitness. The complexes from the model parasite Toxoplasma gondii were inhibited with the antimalarial atovaquone, revealing interactions underpinning species specificity. They were also inhibited with endochin-like quinolone (ELQ)-300, an inhibitor in late-stage preclinical development. Notably, in the apicomplexan binding site, ELQ-300 is flipped compared with related compounds in the mammalian enzyme. On the basis of the binding modes and parasite-specific interactions discovered, we designed more potent ELQs with subnanomolar activity against T. gondii. Our findings reveal critical evolutionary differences in the role of supercomplexes in mitochondrial biology and provide insight into cytochrome b inhibition, informing future drug discovery.
    DOI:  https://doi.org/10.1038/s41594-025-01531-7
  3. Parasit Vectors. 2025 May 20. 18(1): 181
    Toxoplasma calcium-dependent protein kinases 3 mediates M1 macrophage polarization by targeting host Arginase-1.
    Ran An, Fang Liu, Niuniu Dai, Fangmin Li, Xingyun Liu, Haijian Cai, Lijian Chen, Jian Du.
       BACKGROUND: Toxoplasma gondii, an obligate intracellular parasite, has developed sophisticated ways to manipulate host immunity, resulting in long-lasting infection and causing serious public health problems in humans and animals. T. gondii type II is the type most frequently associated with human diseases, but the mechanism remains unclear. Toxoplasma calcium-dependent protein kinase 3(CDPK3), a protein located on the T. gondii parasite periphery, is highly expressed in type II strains. Although TgCDPK3 regulates parasite egress from host cells, calcium-based infiltration, and development of tissue cysts, the host target proteins that it modulates are still unclear.
    METHODS: Firstly, mass spectrometry was used to analyze proteins that selectively bind to TgCDPK3. Subsequently, GST (glutathione-s-transferase) pull-down, immunoprecipitation, and immunofluorescence assay were used to confirm the interaction and colocalization between TgCDPK3 and Arginase-1. Western blotting and Argininaseactivity assays were performed to detect the relative levels of endogenous Arginase-1 and inducible nitric oxide synthase (iNOS) in a murine microglial cell line. Fluorescence activated cell sorting (FACS) assays and enzyme-linked immunosorbent assay (ELISA) analysis were performed to confirm the association of interaction between TgCDPK3 and Arginase-1 within an M1/M2-polarized macrophage. Intracellular multiplication assays and plaque assays were performed to test whether the interaction between TgCDPK3 and Arginase-1 affected intercellular parasite growth.
    RESULTS: The interaction between TgCDPK3 and Arginase-1 is functionally correlated and leads to a reduction in Arginase-1 activity, ultimately, contributing to the M1-biased phenotype of the host macrophages, which is related to restraining the proliferation of parasites.
    CONCLUSIONS: Our data showed that CDPK3 mediates M1 macrophage polarization by targeting host Arginase-1, which is beneficial to understanding the mechanism for long term latency establishment of less virulent strains of Toxoplasma.
    Keywords:   Toxoplasma gondii ; Arginase-1; CDPK3; Macrophages polarization; Proliferation
    DOI:  https://doi.org/10.1186/s13071-025-06799-8
  4. Microb Biotechnol. 2025 May;18(5): e70143
    Toxoplasma gondii C2 Domain Protein Deletion Mutant as a Promising Vaccine Against Toxoplasmosis in Mice.
    Yifan Luo, Mingfeng He, Shengqiang Yang, Jiahui Qian, Zhengming He, Jiayin Xu, Liyu Guo, Siyu Xiao, Rui Fang.
      Toxoplasma gondii (T. gondii), a parasitic protozoan capable of infecting nearly all warm-blooded animals, causes significant economic losses in livestock and poses a significant threat to both animal and public health. Despite its impact, no ideal vaccine is currently available to prevent toxoplasmosis. Vesicular transport plays a crucial role in the life cycle of T. gondii, and proteins involved in this process - such as those containing C2 domains - may serve as novel targets for the development of live attenuated vaccines. In this study, we evaluated the feasibility of a C2 domain-containing protein (TGME49_203240) as a live attenuated vaccine candidate. Our findings suggest that TGME49_203240 may be involved in vesicular transport and that it is essential for T. gondii growth. Deletion of TGME49_203240 reduced parasite virulence and impaired tissue cyst formation in mice. Moreover, mice vaccinated with ME49Δ203240 were protected against the lethal challenge of the tachyzoites of T. gondii I, II, III strains and cysts of II strain. In addition, the ME49Δ203240 strain elicited robust immune responses, including the production of high levels of specific IgG antibodies and key cytokines (IFN-γ, TNF-α and IL-12). These findings highlight TGME49_203240 as a promising target for the development of a live attenuated vaccine against T. gondii.
    Keywords:   Toxoplasma gondii ; C2 domain; TGME49_203240; immune protection; live attenuated vaccine; vesicle transport
    DOI:  https://doi.org/10.1111/1751-7915.70143
  5. mBio. 2025 May 23. e0099425
    TcCARP3 modulates compartmentalized cAMP signals involved in osmoregulation, infection of mammalian cells, and colonization of the triatomine vector in the human pathogen Trypanosoma cruzi.
    Joshua Carlson, Milad Ahmed, Riley Hunter, Syeda Farjana Hoque, Joshua B Benoit, Miguel A Chiurillo, Noelia Lander.
      Trypanosoma cruzi is the causative agent of Chagas disease, a zoonotic infectious disease considered a leading cause of cardiomyopathy, disability, and premature death in the Americas. This parasite spends its life between a mammalian host and an arthropod vector, undergoing essential transitions among different developmental forms. How T. cruzi senses microenvironmental changes that trigger cellular responses necessary for parasite survival has remained largely unknown. Cyclic AMP (cAMP) is a universal second messenger that has been shown to regulate key cellular processes in trypanosomes, in which cAMP response proteins (CARPs) have been proposed to be modulators or effectors of a PKA-independent signaling pathway. In this study, we aimed to investigate the role of TcCARP3 in cAMP signaling throughout the T. cruzi life cycle. Our results show that TcCARP3 shares a dual localization (flagellar tip and contractile vacuole complex) with adenylate cyclase 1 (TcAC1) in the main developmental stages of the parasite. We also found that TcCARP3 directly interacts with several TcACs, modulating the intracellular content of cAMP. Through generation of TcCARP3 knockout, addback, and overexpression cell lines, we showed that modulation of gene expression affects the parasite's ability to differentiate, respond to osmotic stress, invade mammalian cells and replicate within them, and colonize the hindgut of the triatomine vector. In addition, we identified several signaling proteins interacting with TcCARP3 in what we propose are cAMP signaling microdomains. Our results unveil a key role for TcCARP3 as a modulator of cAMP signals necessary for parasite differentiation and survival throughout the T. cruzi life cycle.IMPORTANCECyclic AMP (cAMP) signaling pathways are poorly understood in the stercorarian parasite Trypanosoma cruzi. Specifically, the mechanisms driving the activation of TcACs in response to microenvironmental stress are completely unknown. This study unveils the role of TcCARP3 in modulating the content of cAMP through the interaction with several TcACs and putative cAMP effectors in T. cruzi. Particularly, TcCARP3 interacts with TcAC1 in the main developmental stages of this parasite's life cycle, where both proteins display a dual localization pattern. These results provide new evidence supporting the compartmentalization of cAMP signals in trypanosomes. Moreover, our data unequivocally demonstrates that TcCARP3 is required for essential cellular processes, such as response to osmotic stress, host cell invasion, intracellular replication, and the ability to colonize the hindgut of the triatomine vector. In summary, we found that TcCARP3 is an adenylate cyclase interactor that modulates cAMP signals necessary for the life cycle progression of T. cruzi.
    Keywords:  Chagas disease; adenylate cyclase; contractile vacuole complex; flagellar distal domain; kissing bugs; metacyclogenesis; regulatory volume decrease; trypanosomes
    DOI:  https://doi.org/10.1128/mbio.00994-25
  6. Methods Enzymol. 2025 ;pii: S0076-6879(25)00069-2. [Epub ahead of print]715 337-349
    Cell-based determination of HDAC10-mediated polyamine deacetylase activity.
    Ishika Gupta, Ashley Nwafor, Robert A Casero, Tracy Murray Stewart.
      Among histone deacetylases, HDAC10 is unique in its substrate preference for a specific acetylated polyamine, N8-acetylspermidine (N8-AcSpd), over other acetylated polyamines and peptides. As a polyamine deacetylase, HDAC10 catalyzes the conversion of N8-AcSpd into spermidine, thereby enabling the cell to utilize this acetylated derivative to support polyamine homeostasis. Therefore, the level of HDAC10-mediated PDAC activity in a particular tissue and its exposure to extracellular N8-AcSpd, a byproduct of certain intestinal microbes, may directly contribute to the maintenance of intracellular polyamine concentrations. This chapter provides detailed methods for determining relative levels of HDAC10-mediated polyamine deacetylase activity using cell-based assays. These cost-efficient methods are useful for identifying tissue-specific differences in PDAC activity and may also be adapted to enable high-throughput screening of effectors of HDAC10 function, such as HDAC inhibitors.
    Keywords:  HDAC10 assay; Histone deacetylase 10; N8-acetylspermidine; Polyamine deacetylase; Spermidine metabolism
    DOI:  https://doi.org/10.1016/bs.mie.2025.01.047
  7. Methods Enzymol. 2025 ;pii: S0076-6879(25)00084-9. [Epub ahead of print]715 41-63
    TR-FRET assay for profiling HDAC10 inhibitors and PROTACs.
    Kim Remans, Peter Sehr, Raphael R Steimbach, Nikolas Gunkel, Aubry K Miller.
      Quantitative biochemical characterization of the binding/inhibitory properties of investigative substances against their protein targets and anti-targets is a necessary step in modern drug discovery campaigns. The histone deacetylase family of proteins comprises eleven Zn2+ dependent enzymes, members of which are regularly investigated as therapeutic drug targets. The binding of histone deacetylases by small molecule inhibitors or PROTACs is typically measured in enzymatic assays that use acylated lysine-containing peptides as substrates. Histone deacetylase 10, however, is unique within the family in that it recognizes acetylated small molecule polyamines, as opposed to peptides, as substrates. We have therefore adapted a TR-FRET ligand displacement assay for histone deacetylase 10, which does not rely on enzymatic turnover of a substrate. In this chapter, we describe the preparation of the three different assay components: a small molecule dye conjugate "tracer", a TwinStrep-GST-HDAC10 fusion protein, and Eu3+-labelled Strep-TactinXT®. Lastly, we describe how to combine these reagents and perform dose-response measurements of investigational HDAC10-binding molecules to produce IC50 values.
    Keywords:  Assay development; Drug discovery; HDAC10; Histone deacetylase; TR-FRET
    DOI:  https://doi.org/10.1016/bs.mie.2025.01.061
  8. PLoS One. 2025 ;20(5): e0323242
    Dynamic metabolic regulation of histone modifications during the yeast metabolic cycle.
    Bárbara Guzmán-Dinamarca, Raúl Conejeros, Marcelo Rivas-Astroza.
      Eukaryotes achieve a wide range of stable phenotypes by virtue of epigenetic modifications. However, what drives epigenetic diversification in the first place remains an open question. Here, we investigated the dynamic interplay between the production fluxes of epigenetic cosubstrates and histone post-translation modifications (PTMs) in Saccharomyces cerevisiae's Yeast Metabolic Cycle (YMC). We developed a novel approach integrating flux analysis with transcriptomic data to investigate the production fluxes of acetyl-CoA and SAM and their influence on histone marks H3K9Ac and H3K4me3. Our results show that acetyl-CoA and SAM flux dynamics are asynchronous during the YMC, suggesting distinct regulatory roles. Gene ontology analysis revealed that genes whose enrichment of H3K9Ac correlates with acetyl-CoA dynamics are associated with metabolic functions, while genes whose enrichment of H3K4me3 correlates with SAM dynamics are associated with translation processes. Finally, we found evidence that chromatin accessibility on genes promoter regions was a precondition for the metabolic fluxes influencing the enrichment of H3K4me3 and H3K9Ac. These findings support the concept that metabolism provides timely cosubstrates essential for histone PTMs.
    DOI:  https://doi.org/10.1371/journal.pone.0323242
  9. Nat Commun. 2025 May 23. 16(1): 4790
    PfPPM2 signalling regulates asexual division and sexual conversion of human malaria parasite Plasmodium falciparum.
    Akanksha Rawat, Neelam Antil, Meenakshi, Bhagyashree Deshmukh, Akhila Balakrishna Rai, Annu Nagar, Narendra Kumar, T S Keshava Prasad, Krishanpal Karmodiya, Pushkar Sharma.
      Malaria parasite undergoes interesting developmental transition in human and mosquito host. While it divides asynchronously in the erythrocytes, it switches to sexual forms, which is critical for disease transmission. We report a novel signalling pathway involving Protein Phosphatase PfPPM2, which regulates asexual division of Plasmodium falciparum as well as its conversion to sexual forms. PfPPM2 may regulate the phosphorylation of key proteins involved in chromatin remodelling and protein translation. One of the key PfPPM2-targets was Heterochromatin Protein 1 (HP1), a regulator of heritable gene silencing which contributes to both mitotic proliferation as well as sexual commitment of the parasite. PfPPM2 promotes sexual conversion by regulating the interaction between HP1, H3K9me3 and chromatin and it achieves this by dephosphorylating S33 of HP1. PfPPM2 also regulates protein synthesis in the parasite by repressing the phosphorylation of initiation factor eIF2α, which is likely to contribute to parasite division and possibly sexual differentiation.
    DOI:  https://doi.org/10.1038/s41467-025-59476-w
  10. Cureus. 2025 Apr;17(4): e82663
    Sirtuin Expression in Age-Associated Hepatic Response to Burn Trauma: Translational and Clinical Insights From a Murine Model.
    Kenneth Meza Monge, Andrea C Qualman, Akshay Pratap, Elizabeth J Kovacs, Juan-Pablo Idrovo.
      Background Burn injuries can lead to substantial liver damage, and this response appears to worsen with age. Although clinical patterns suggest that older individuals are more susceptible to poor outcomes, the biological mechanisms contributing to this increased vulnerability are poorly understood. Sirtuins, a family of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes involved in cellular stress regulation, metabolism, and aging, may play a key role in modulating the hepatic response to burn injury. This study explores the potential mechanistic involvement of sirtuins in age-related liver damage following thermal injury. Methods Female C57BL/6 mice (young: four months; aged: 20-22 months) underwent sham or 15% total body surface area scald burn. Liver tissue was collected at 24- and 48-hours post-injury for quantitative polymerase chain reaction (qPCR) analysis of all seven sirtuin family members. Results Burn injury significantly altered hepatic sirtuin expression in an age- and time-dependent manner. Inflammatory regulators, Sirt1 and Sirt2, showed immediate downregulation in young mice with partial recovery at 48 hours, while aged mice exhibited delayed, more profound, and persistent suppression. In contrast, mitochondrial sirtuins (Sirt3-5) were downregulated in both age groups, and only young burned mice showed recovery of Sirt3 and Sirt4 expression at 48 hours. The most pronounced age-dependent difference occurred with Sirt4. At this time point, the expression of Sirt4 was 71% higher in young burned mice compared to aged injured counterparts (p < 0.05). Genome stability regulating Sirt6 and Sirt7 exhibited age-specific responses, with Sirt6 remaining stable in young injured mice, while Sirt7 was lower in aged mice at 48 hours (p < 0.05). Conclusion This study reveals for the first time that burn injury triggers age-dependent alterations in the pattern of hepatic sirtuin expression, with delayed and/or more severe and persistent suppression across all sirtuin family members. These findings provide new mechanistic insights into the dysregulation of critical cellular homeostatic mechanisms in aged livers following burn injury and identify sirtuins as potential therapeutic targets for mitigating age-associated hepatic damage in elderly burn patients.
    Keywords:  aging; apoptosis; burn injury; gene expression; hepatic damage; inflammation; liver injury; oxidative stress; sirtuins; trauma
    DOI:  https://doi.org/10.7759/cureus.82663
  11. Int J Biol Sci. 2025 ;21(7): 2973-2990
    SIRT4 Controls Acetyl-CoA Synthesis to Promote Stemness and Invasiveness of Hepatocellular Carcinoma through Deacetylating MCCC2.
    Tianjiao Sun, Congcong Xu, Qingru Song, Xiaodan Yang, Guo An, Guogui Sun, Zhiqian Zhang.
      SIRT4 is well-known as a tumor suppressor by controlling several metabolic pathways, although it is highly expressed in certain cancers including hepatocellular carcinoma (HCC). Here, we reported that SIRT4 was highly expressed in the voltage-gated calcium channel α2δ1 subunit-positive HCC tumor-initiating cells (TIC), and was upregulated by α2δ1-mediated calcium signaling. Moreover, the expression of SIRT4 in HCC tissues was predictive of poor prognosis of the patients. Interestingly, SIRT4 was functionally sufficient and indispensable to promote TIC properties and invasiveness of HCC cells by directly deacetylating the leucine catabolism pathway enzyme-3-methylcrotonyl-CoA carboxylase 2 (MCCC2) at K269, leading to the formation of a stable MCCC1/MCCC2 complex with robust MCCC enzymatic activity to produce more acetyl-CoA, which resulted in increased H3K27 acetylation and stem cell-like properties at doses≤2 µM. However, 10 µM acetyl-CoA was neither able to enhance H3K27 acetylation, nor to promote stem cell-like properties, while forced expression of SIRT4 in α2δ1+ cells resulted in retardation of tumor growth in vivo. Thus, SIRT4 serves as an oncogene to promote stemness and invasiveness by controlling the production of acetyl-CoA, linking α2δ1-mediated calcium signaling to SIRT4-mediated epigenetic reprogramming of HCC TICs which hold significant potential for the development of novel therapeutic strategies targeting TICs, and the dual roles of SIRT4 in HCC might be dependent on the production levels of acetyl-CoA.
    Keywords:  Acetyl-CoA; MCCC2; SIRT4; cancer stem cells; hepatocellular carcinoma
    DOI:  https://doi.org/10.7150/ijbs.99004
  12. mBio. 2025 May 20. e0221524
    Energy metabolism in Trypanosoma cruzi: the validated and putative bioenergetic and carbon sources.
    Mayke B Alencar, Sabrina Marsiccobetre, Ana C Mengarda, Maria Sol Ballari, Ariel M Silber.
      Trypanosoma cruzi, along with Trypanosoma brucei and over 20 species of the genus Leishmania, constitutes a group of human pathogenic flagellated protists collectively called the "TriTryp," posing among the best-studied protists. These organisms have complex life cycles and are transmitted by insects, which, along with vertebrates, serve as their natural hosts. Throughout their life cycles, these parasites encounter diverse environments with varying physical, chemical, biochemical, and biological characteristics that serve as stages for their evolutionary stories, culminating in different metabolic configurations and requirements. Here, we review the evidence for metabolic pathways that directly or indirectly participate in energy-transducing processes, discussing where appropriate the implications of the different metabolic networks in TriTryp.
    Keywords:  Chagas disease; Trypanosoma cruzi; amino acid metabolism; bioenergetics; carbohydrate metabolism; glycosome; mitochondria
    DOI:  https://doi.org/10.1128/mbio.02215-24
  13. Cancer Immunol Immunother. 2025 May 22. 74(7): 212
    Molecular mimicry between parasites and cancer: a novel approach for developing cancer vaccines and therapeutic antibodies.
    Maha Mohamed Eissa, Sonia Rifaat Ahmed Allam, Cherine Adel Ismail, Rasha Abdelmawla Ghazala, Nahla El Skhawy, Eman Ibrahim El-Said Ibrahim.
      Cancer is one of the most dreaded diseases worldwide. Conventional treatments such as surgery, chemotherapy, and radiotherapy have limitations and adverse effects. Cancer immunotherapy and targeted therapies offer new treatment options. Parasite-based cancer therapy shows promise in fighting tumors. Some parasites have anti-cancer properties through multi-mechanistic strategies, with the molecular mimicry theory as a leading explanation for parasites' anti-cancer effects. This study aimed to explore the existence of shared antigenic proteins between parasites (Trichinella spiralis, Schistosoma mansoni, and Toxoplasma gondii) and cancer cell lines (MCF-7 human breast cancer and A549 human lung cancer). Polyclonal antisera against T. spiralis, S. mansoni, and T. gondii parasites were generated in rabbits. Antibody reactivity with extracts of MCF-7 and A549 cancer cells was detected using SDS-PAGE and immunoblotting. Results documented the molecular mimicry between parasites and cancers as it revealed cross-reactive bands when using T. spiralis antibodies against MCF-7 and A549 cancer cell extracts at approximate molecular weights of 70 and 35 kDa, and with S. mansoni antibodies at an approximate molecular weight of 80 kDa. Toxoplasma gondii antibodies neither reacted with MCF-7 human breast cancer nor A549 human lung cancer cell extracts. Results of this study could establish a foundation for subsequent investigation among a broad range of parasites for molecular mimicry with cancers. Identification, molecular characterization, and investigation of the anti-neoplastic activity of these cross-reactive antigens could shed light on new pathways for the potential development of a novel class of innovative cancer vaccine candidates and therapeutic antibodies of parasitic origin for cancer immunotherapy and targeted therapy.
    Keywords:  Cancer; Cancer therapy; Molecular mimicry; Parasites
    DOI:  https://doi.org/10.1007/s00262-025-04069-1
  14. Hemasphere. 2025 May;9(5): e70134
    Metabolism in hematology: Technological advances open new perspectives on disease biology and treatment.
    Eileen Haring, Joerg M Buescher, Petya Apostolova.
      The term metabolism refers to the multi-faceted biochemical reactions within a cell or an organism that occur to maintain energy homeostasis, cell growth, and oxidative balance. Cells possess a high metabolic plasticity, allowing them to adapt to the dynamic requirements of their functional state and environment. Deregulated cellular metabolism is a hallmark of many diseases, including benign and malignant hematological conditions. In the last decade, multiple technological innovations in the metabolism field have made in-depth metabolic analysis broadly applicable. Such studies are shedding new light on normal and malignant hematopoiesis and open avenues to a better understanding of the biology of hematological diseases. In this review, we will first give a brief overview of central metabolic processes. Furthermore, we discuss the most commonly used methods to study metabolism. We begin by elaborating on the use of next-generation sequencing to detect metabolism-related genomic mutations and study transcriptional signatures. Furthermore, we discuss methods for measuring protein expression, such as mass spectrometry (MS), flow cytometry, and cytometry time-of-flight. Next, we describe the use of nuclear magnetic resonance spectroscopy, MS, and flow cytometry for metabolite quantification. Finally, we highlight functional assays to probe metabolic pathways in real-time. We illustrate how these technologies and their combination have advanced our understanding of the role of metabolism. Our goal is to provide hematologists with a comprehensive guide to modern techniques in metabolism research, their benefits and disadvantages, and how they guide our understanding of disease and potentially future personalized therapy decisions.
    DOI:  https://doi.org/10.1002/hem3.70134
  15. Mol Syst Biol. 2025 May 22.
    An enzyme activation network reveals extensive regulatory crosstalk between metabolic pathways.
    Sultana Mohammed Al Zubaidi, Muhammad Ibtisam Nasar, Richard A Notebaart, Markus Ralser, Mohammad Tauqeer Alam.
      Enzyme activation by cellular metabolites plays a pivotal role in regulating metabolic processes. Nevertheless, our comprehension of such activation events on a global network scale remains incomplete. In this study, we conducted a comprehensive investigation into the optimization of cell-intrinsic activation interactions using Saccharomyces cerevisiae metabolic network as the basis of the analysis. To achieve this, we integrated a genome-scale metabolic model with cross-species enzyme kinetic data sourced from the BRENDA database, and to use this model as a basis to estimate the distribution of enzyme activators throughout the cellular network. Our findings indicate that the vast majority of biochemical pathways encompass enzyme activators, frequently originating from disparate pathways, thus revealing extensive regulatory crosstalk between metabolic pathways. Notably, activators have short pathway lengths, indicating they are activated quickly upon nutrient shifts, and in most instances, these activators target key enzymatic reactions to facilitate downstream metabolic processes. Interestingly, highly activated enzymes are substantially enriched with non-essential enzymes compared to their essential counterparts. This observation suggests that cells employ enzyme activators to finely regulate secondary metabolic pathways that are only required under specific conditions. Conversely, the activator metabolites themselves are more likely to be essential components, and their activation levels surpass those of non-essential activators. In summary, our study unveils the widespread importance of enzymatic activators and suggests that feed-forward activation of conditional metabolic pathways through essential metabolites mediates metabolic plasticity.
    Keywords:  Activator Compounds; Intracellular Activation Network; Metabolic Network; Metabolic Regulation; Regulatory Crosstalk
    DOI:  https://doi.org/10.1038/s44320-025-00111-7
  16. Cell Rep. 2025 May 19. pii: S2211-1247(25)00493-0. [Epub ahead of print]44(6): 115722
    MYC plus class IIa HDAC inhibition drives mitochondrial dysfunction in non-small cell lung cancer.
    Jina Park, Ying-Yu Chen, Jennie J Cao, Julia An, Ray-Whay Chiu Yen, John D Outen, Stephen B Baylin, Michael J Topper.
      Despite much progress in targeting the MYC oncoprotein, combination treatment strategies are needed to exploit this molecular vulnerability. To this end, we interrogated transcriptome data from cancer cell lines treated with MYC inhibitors and identified HDAC5 and HDAC9, both class IIa histone deacetylases (HDACs), as potential therapeutic targets. Notably, these therapeutically actionable HDAC isoforms are known augmenters of several hallmarks of cancer. Dual targeting of MYC and class IIa HDACs induces a significant reduction in viability for non-small cell lung cancer (NSCLC) cell lines with high MYC and mitochondrial activity. Additionally, combination treatment induces a robust MYC suppression with mitochondrial reactive oxygen species (ROS) elevation, which has a causal relationship with therapeutic efficacy. Confirmation of in vivo efficacy was pursued in several animal models, with subsequent molecular-correlate derivation confirming the importance of MYC depletion and mitochondrial dysfunction in drug efficacy. Ultimately, we define a therapeutic approach combining MYC- and class IIa HDAC-inhibition to potentiate anti-tumor efficacy in NSCLC.
    Keywords:  CP: Cancer; MYC; class IIa HDAC; mitochondria; non-small lung cancer; oxidative stess
    DOI:  https://doi.org/10.1016/j.celrep.2025.115722
  17. Bot Stud. 2025 May 22. 66(1): 14
    Analysing protein complexes in plant science: insights and limitation with AlphaFold 3.
    Pei-Yu Lin, Shiang-Chin Huang, Kuan-Lin Chen, Yu-Chun Huang, Chia-Yu Liao, Guan-Jun Lin, HueyTyng Lee, Pao-Yang Chen.
      AlphaFold 3 (AF3), an artificial intelligence (AI)-based software for protein complex structure prediction, represents a significant advancement in structural biology. Its flexibility and enhanced scalability have unlocked new applications in various fields, specifically in plant science, including improving crop resilience and predicting the structures of plant-specific proteins involved in stress responses, signalling pathways, and immune responses. Comparisons with existing tools, such as ClusPro and AlphaPulldown, highlight AF3's unique strengths in sequence-based interaction predictions and its greater adaptability to various biomolecular structures. However, limitations persist, including challenges in modelling large complexes, protein dynamics, and structures from underrepresented plant proteins with limited evolutionary data. Additionally, AF3 encounters difficulties in predicting mutation effects on protein interactions and DNA binding, which can be improved with molecular dynamics and experimental validation. This review presents an overview of AF3's advancements, using examples in plant and fungal research, and comparisons with existing tools. It also discusses current limitations and offers perspectives on integrating molecular dynamics and experimental validation to enhance its capabilities.
    Keywords:  AlphaFold 3; Crop resilience; Protein complex; Protein structure; Protein–protein interaction; Structure biology
    DOI:  https://doi.org/10.1186/s40529-025-00462-2
  18. J Biol Chem. 2025 May 17. pii: S0021-9258(25)02100-3. [Epub ahead of print] 110250
    Biochemical Impact of p300-Mediated Acetylation of Replication Protein A: Implications for DNA Metabolic Pathway Choice.
    Onyekachi Ononye, Sneha Surendran, Tripthi Battapadi, Pamela VanderVere-Carozza, Olivia K Howald, Athena Kantartzis-Petrides, Matthew R Jordan, Diana Ainembabazi, Marc S Wold, John J Turchi, Lata Balakrishnan.
      Replication Protein A (RPA), a single-stranded DNA (ssDNA) binding protein, is vital for various aspects of genome maintenance such as replication, recombination, repair and cell cycle checkpoint activation. Binding of RPA to ssDNA protects it from degradation by cellular nucleases, prevents secondary structure formation and suppresses illegitimate recombination. In our current study, we identified the acetyltransferase p300 to be capable of acetylating the 70kDa subunit of RPA in vitro and within cells. The acetylation status of RPA changes throughout the cell cycle, increasing during the S and G2/M phases, and after UV-induced damage. Furthermore, we were able to specifically identify RPA directly associated with the replication fork during the S phase and UV damage to be acetylated. Based on these observations, we evaluated the impact of lysine acetylation on the biochemical properties of RPA. Investigation of binding properties of RPA revealed that acetylation of RPA increased its binding affinity to ssDNA compared to unmodified RPA. The improvement in binding efficiency was a function of DNA length with the greatest increases observed on shorter length ssDNA oligomers. Enzymatic assays further revealed that upon acetylation RPA governs the switch between the short and long flap pathway for Okazaki fragment processing. Our findings demonstrate that p300-dependent, site-specific acetylation enhances RPA's DNA binding properties, potentially regulating its function during various DNA transactions.
    Keywords:  G1/S phase; Replication Protein A (RPA); UV-induced damage; lysine acetylation; p300; single-strand DNA binding
    DOI:  https://doi.org/10.1016/j.jbc.2025.110250
  19. Curr Opin Cell Biol. 2025 May 16. pii: S0955-0674(25)00067-5. [Epub ahead of print]95 102529
    Mechano-metabolism on the rise.
    Sirio Dupont.
      Cells respond to the physical and geometrical tissue properties by multiple mechanotransduction mechanisms that can profoundly influence cells' decision-making, extending to cell metabolism. This review incorporates the most recent findings on this topic, organized along the idea that the mechano-metabolic connection serves three main functions, namely to inform systemic metabolism on the general functioning of a tissue/organ, to tune cells' energy production with the mechanical requirements imposed by their surroundings, and to coordinate cell metabolism with cell fate choices induced in response to mechanical cues. This connection highlights the pervasive influence of mechanical cues on cell activity, opens interesting questions on its physiological and pathological roles, and lays the foundations for exploiting the mechano-metabolism axis to design new therapeutic approaches.
    DOI:  https://doi.org/10.1016/j.ceb.2025.102529
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