Affinage

CS

Citrate synthase, mitochondrial · UniProt O75390

Length
466 aa
Mass
51.7 kDa
Annotated
2026-06-09
100 papers in source corpus 2 papers cited in narrative 2 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 3/3 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Citrate synthase (CS) is a mitochondrial enzyme whose activity gates TCA cycle flux and thereby couples mitochondrial metabolism to cell-state decisions in immune and cancer cells (PMID:37820280, PMID:38693171). In macrophages, HBV stimulation downregulates the mitochondrial deacetylase SIRT3 through a TLR2–NF-κB–PGC-1α axis, leading to hyperacetylation of CS that inhibits its enzymatic activity, impairs the TCA cycle, and drives M2-like polarization; restoring TCA flux with dichloroacetate reverses this polarization and lowers viral load in vivo (PMID:37820280). In nasopharyngeal carcinoma cells, CS expression is suppressed by miR-122-5p, and loss of CS sensitizes cells to erastin-induced ferroptosis, marked by increased lipid peroxidation, iron accumulation, ROS, and glutathione depletion (PMID:38693171). Beyond these acetylation-dependent and expression-level controls of CS activity, no further mechanistic detail on CS has been characterized in the available corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 2 steps
  1. 2023 Medium

    Established that CS activity is controlled post-translationally by acetylation and that this control links viral signaling to macrophage metabolic reprogramming, answering how HBV reshapes immune cell fate through the TCA cycle.

    Evidence Immunoprecipitation of acetylated CS, enzymatic activity assays, metabolomics, and an in vivo chronic HBV mouse model with dichloroacetate rescue

    PMID:37820280

    Open questions at the time
    • Specific acetylated lysine residues on CS not mapped
    • Direct SIRT3–CS deacetylation not reconstituted biochemically
    • Single lab, no independent replication
  2. 2024 Medium

    Established that CS expression level tunes ferroptosis sensitivity, answering how a metabolic enzyme influences lipid peroxidation-driven cell death in cancer.

    Evidence miR-122-5p gain/loss-of-function, CS knockdown/overexpression with ferroptosis readouts (MDA, Fe2+, GSH, ROS, mitochondrial morphology), and in vivo NPC xenograft

    PMID:38693171

    Open questions at the time
    • Mechanism linking CS metabolic output to lipid peroxidation not defined
    • Whether the effect depends on CS catalytic activity vs. protein level untested
    • Single lab and single tumor context

Open questions

Synthesis pass · forward-looking unresolved questions
  • Whether acetylation-dependent regulation of CS and CS-dependent control of ferroptosis represent a unified metabolic mechanism across cell types remains unresolved.
  • No structural model of regulated CS
  • Acetylation sites unmapped
  • Connection between TCA flux and lipid peroxidation pathway not mechanistically traced

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 1
Localization
GO:0005739 mitochondrion 1
Pathway
R-HSA-1430728 Metabolism 2

Evidence

Reading pass · 2 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 HBV stimulation causes hyperacetylation of citrate synthase (CS) in macrophages, which inhibits CS enzymatic activity, impairs the TCA cycle, and drives M2-like macrophage polarization. HBV downregulates SIRT3 (a mitochondrial deacetylase) via the TLR2–NF-κB–PGC-1α axis, resulting in CS hyperacetylation; restoration of TCA cycle activity with dichloroacetate reversed M2 polarization and reduced serum HBV DNA in vivo. Immunoprecipitation (to detect acetylation of CS), western blot, metabolomics, flow cytometry, in vivo chronic HBV mouse model with dichloroacetate treatment Hepatology communications Medium 37820280
2024 miR-122-5p overexpression suppresses citrate synthase (CS) expression in nasopharyngeal carcinoma (NPC) cells, and this suppression promotes erastin-induced ferroptosis, as measured by increased lipid peroxidation markers (MDA, Fe2+, ROS), decreased glutathione, and mitochondrial morphology changes; the effect was confirmed in a subcutaneous mouse NPC model. miR-122-5p overexpression/silencing, CS knockdown/overexpression, ferroptosis assays (MDA, Fe2+, GSH, ROS, mitochondrial morphology), cell proliferation/migration assays, in vivo mouse xenograft Scientific reports Medium 38693171

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The atypical protein kinase Cs. Functional specificity mediated by specific protein adapters. EMBO reports 197 11258478
1991 Protection against malaria by vaccination with sporozoite surface protein 2 plus CS protein. Science (New York, N.Y.) 182 1827210
1999 Ca2+-calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. Trends in neurosciences 121 10088994
2001 Synthetic lethality between mutation in Atm and DNA-PK(cs) during murine embryogenesis. Current biology : CB 118 11231155
1987 CS-A therapy in MRL-lpr/lpr mice: amelioration of immunopathology despite autoantibody production. Journal of immunology (Baltimore, Md. : 1950) 114 3537128
2004 Consolidation of CS and US representations in associative fear conditioning. Hippocampus 112 15301434
2006 Autophagy, bafilomycin and cell death: the "a-B-cs" of plecomacrolide-induced neuroprotection. Autophagy 103 16874105
2018 The C-S-A gene system regulates hull pigmentation and reveals evolution of anthocyanin biosynthesis pathway in rice. Journal of experimental botany 96 29361187
2007 Isoform specificity of protein kinase Cs in synaptic plasticity. Learning & memory (Cold Spring Harbor, N.Y.) 90 17404386
2021 Chitosan-Selenium Nanoparticle (Cs-Se NP) Foliar Spray Alleviates Salt Stress in Bitter Melon. Nanomaterials (Basel, Switzerland) 89 33803416
2007 Priming with an adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone. Infection and immunity 85 17307942
2018 The C/S1 bZIP Network: A Regulatory Hub Orchestrating Plant Energy Homeostasis. Trends in plant science 84 29525129
2014 The effects of Nigella sativa (Ns), Anthemis hyalina (Ah) and Citrus sinensis (Cs) extracts on the replication of coronavirus and the expression of TRP genes family. Molecular biology reports 84 24413991
2012 The Trk A, B, C's of neurotrophins in the cochlea. Anatomical record (Hoboken, N.J. : 2007) 83 23044862
2011 Magnetic biodegradable Fe3O4/CS/PVA nanofibrous membranes for bone regeneration. Biomedical materials (Bristol, England) 75 21893702
1996 Acute and chronic effects of troglitazone (CS-045) on isolated rat ventricular cardiomyocytes. Diabetologia 74 8817100
2008 Tear gasses CN, CR, and CS are potent activators of the human TRPA1 receptor. Toxicology and applied pharmacology 73 18501939
1997 Ca2+ differentially regulates conventional protein kinase Cs' membrane interaction and activation. The Journal of biological chemistry 70 9325330
2019 The Dual Roles of the Atypical Protein Kinase Cs in Cancer. Cancer cell 69 31474570
2015 The A, B, Cs of herpesvirus capsids. Viruses 61 25730559
1994 Rapid clearance of malaria circumsporozoite protein (CS) by hepatocytes. The Journal of experimental medicine 60 8294876
1994 Inactive membrane protein kinase Cs: a possible target for receptor signalling. The Biochemical journal 55 7818485
2019 Radical-mediated C-S bond cleavage in C2 sulfonate degradation by anaerobic bacteria. Nature communications 53 30962433
2004 The role of lipids and protein kinase Cs in the pathogenesis of diabetic retinopathy. Diabetes/metabolism research and reviews 53 14737743
2013 Chitosan tripolyphosphate (CS/TPP) nanoparticles: preparation, characterization and application for gene delivery in shrimp. Acta tropica 51 23906611
2012 BAF60 A, B, and Cs of muscle determination and renewal. Genes & development 51 23222103
2003 Cholesterol and tau protein--findings in Alzheimer's and Niemann Pick C's disease. Pharmacopsychiatry 50 14574625
2013 Cigarette smoke (CS) and nicotine delay neutrophil spontaneous death via suppressing production of diphosphoinositol pentakisphosphate. Proceedings of the National Academy of Sciences of the United States of America 48 23610437
2014 A phase Ia study to assess the safety and immunogenicity of new malaria vaccine candidates ChAd63 CS administered alone and with MVA CS. PloS one 47 25522180
2022 Remembering your A, B, C's: Alzheimer's disease and ABCA1. Acta pharmaceutica Sinica. B 46 35530134
2017 Chitosan-lipid nanoparticles (CS-LNPs): Application to siRNA delivery. Journal of colloid and interface science 46 28934610
2006 Cathepsin Cs are key for the intracellular survival of the protozoan parasite, Toxoplasma gondii. The Journal of biological chemistry 46 17164247
1990 Non-CS pre-erythrocytic protective antigens. Immunology letters 46 2283163
2016 Role of Chondroitin Sulfate (CS) Modification in the Regulation of Protein-tyrosine Phosphatase Receptor Type Z (PTPRZ) Activity: PLEIOTROPHIN-PTPRZ-A SIGNALING IS INVOLVED IN OLIGODENDROCYTE DIFFERENTIATION. The Journal of biological chemistry 45 27445335
2011 Discovery of CS-0777: A Potent, Selective, and Orally Active S1P1 Agonist. ACS medicinal chemistry letters 45 24900318
2005 The PatB protein of Bacillus subtilis is a C-S-lyase. Biochimie 44 15760717
2000 The ethylene-regulated expression of CS-ETR2 and CS-ERS genes in cucumber plants and their possible involvement with sex expression in flowers. Plant & cell physiology 44 10929944
2012 Chromosome organization in the nucleus - charting new territory across the Hi-Cs. Current opinion in genetics & development 43 22265226
2015 Repression of CC16 by cigarette smoke (CS) exposure. PloS one 41 25635997
2021 Neural Tissue Homeostasis and Repair Is Regulated via CS and DS Proteoglycan Motifs. Frontiers in cell and developmental biology 40 34409033
1997 The five cleavage-stage (CS) histones of the sea urchin are encoded by a maternally expressed family of replacement histone genes: functional equivalence of the CS H1 and frog H1M (B4) proteins. Molecular and cellular biology 40 9032246
2023 SULT2B1-CS-DOCK2 axis regulates effector T-cell exhaustion in HCC microenvironment. Hepatology (Baltimore, Md.) 39 36626623
2015 C-S bond cleavage by a polyketide synthase domain. Proceedings of the National Academy of Sciences of the United States of America 38 26240335
2019 3D Bio-Printing of CS/Gel/HA/Gr Hybrid Osteochondral Scaffolds. Polymers 37 31574999
2011 Cloning and functional analysis of the naphthomycin biosynthetic gene cluster in Streptomyces sp. CS. Molecular bioSystems 37 21614382
2011 Bortezomib sensitizes HCC cells to CS-1008, an antihuman death receptor 5 antibody, through the inhibition of CIP2A. Molecular cancer therapeutics 36 21393428
1991 Influence of apolipoproteins AI, AII, and Cs on the metabolism of membrane and lysosomal cholesterol in macrophages. The Journal of biological chemistry 36 1657906
2013 Abnormal Ras signaling in Costello syndrome (CS) negatively regulates enamel formation. Human molecular genetics 35 24057668
2020 Fe-TCPP@CS nanoparticles as photodynamic and photothermal agents for efficient antimicrobial therapy. Biomaterials science 34 33103167
2019 CS-PEI/Beclin-siRNA Downregulate Multidrug Resistance Proteins and Increase Paclitaxel Therapeutic Efficacy against NSCLC. Molecular therapy. Nucleic acids 32 31336235
2015 Phase I Imaging and Pharmacodynamic Trial of CS-1008 in Patients With Metastatic Colorectal Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 32 26124477
2000 Membrane translocation of novel protein kinase Cs is regulated by phosphorylation of the C2 domain. The Journal of biological chemistry 32 11073945
2016 Amyloid β induces microglia to phagocytose neurons via activation of protein kinase Cs and NADPH oxidase. The international journal of biochemistry & cell biology 31 27267660
2013 Regulation of Cigarette Smoke (CS)-Induced Autophagy by Nrf2. PloS one 31 23585825
1987 Cloning and characterization of dnaA(Cs), a mutation which leads to overinitiation of DNA replication in Escherichia coli K-12. Journal of bacteriology 30 3040665
2018 CS-ROSETTA. Methods in enzymology 29 30611429
2017 Inhibiting DNA-PKCS radiosensitizes human osteosarcoma cells. Biochemical and biophysical research communications 29 28300555
2004 Expression of the CS- and US-pre-exposure effects in the conditioned taste aversion paradigm and their abolition following systemic amphetamine treatment in C57BL6/J mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 27 15238994
2001 Plasmodium falciparum circumsporozoite (CS) protein peptides specifically bind to HepG2 cells. Vaccine 27 11483275
2019 Three New Cs for CRISPR: Collateral, Communicate, Cooperate. Trends in genetics : TIG 26 31036344
2013 In and out of the bull's eye: protein kinase Cs in the immunological synapse. Trends in immunology 26 23428395
2003 Comparison of CD34+ cell collection on the CS-3000+ and Amicus blood cell separators. Transfusion 26 14507274
2020 Root high-affinity K+ and Cs+ uptake and plant fertility in tomato plants are dependent on the activity of the high-affinity K+ transporter SlHAK5. Plant, cell & environment 25 32275780
2017 Magnetoencephalography with a Cs-based high-sensitivity compact atomic magnetometer. The Review of scientific instruments 24 28964239
2003 Gravity-induced modification of auxin transport and distribution for peg formation in cucumber seedlings: possible roles for CS-AUX1 and CS-PIN1. Planta 23 12905024
2022 A novel yeast strain Geotrichum sp. CS-67 capable of accumulating heavy metal ions. Ecotoxicology and environmental safety 21 35405529
2017 CD146 (MCAM) in human cs-DLK1-/cs-CD34+ adipose stromal/progenitor cells. Stem cell research 21 28549249
2022 Frenkel Excitons in Vacancy-Ordered Titanium Halide Perovskites (Cs2TiX6). The journal of physical chemistry letters 20 36414263
2019 Lyn regulates epithelial-mesenchymal transition in CS-exposed model through Smad2/3 signaling. Respiratory research 20 31477108
1990 Localization of CS and non-CS antigens in the sporogonic stages of Plasmodium yoelii. Bulletin of the World Health Organization 20 2094581
2020 Impact of Prevalence Ratios of Chondroitin Sulfate (CS)- 4 and -6 Isomers Derived from Marine Sources in Cell Proliferation and Chondrogenic Differentiation Processes. Marine drugs 19 32023805
2017 Roles of CSGalNAcT1, a key enzyme in regulation of CS synthesis, in neuronal regeneration and plasticity. Neurochemistry international 19 28987564
1989 Cefmetazole (CS-1170), a "new" cephamycin with a decade of clinical experience. Diagnostic microbiology and infectious disease 19 2692950
2023 Perovskite-Derived Bismuth with I- and Cs+ Dual Modification for High-Efficiency CO2 -to-Formate Electrosynthesis and Al-CO2 Batteries. Advanced materials (Deerfield Beach, Fla.) 18 37272677
2021 Immune system response during viral Infections: Immunomodulators, cytokine storm (CS) and Immunotherapeutics in COVID-19. Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society 18 33519271
2023 HBV suppresses macrophage immune responses by impairing the TCA cycle through the induction of CS/PDHC hyperacetylation. Hepatology communications 17 37820280
2021 Zeta-carbonic anhydrases show CS2 hydrolase activity: A new metabolic carbon acquisition pathway in diatoms? Computational and structural biotechnology journal 17 34194668
2020 Characterization, Biocompatibility, and Optimization of Electrospun SF/PCL/CS Composite Nanofibers. Polymers 17 32605115
2018 Chondroitin Sulfate (CS) Lyases: Structure, Function and Application in Therapeutics. Current protein & peptide science 16 28049392
2023 An S=1 Iron(IV) Intermediate Revealed in a Non-Heme Iron Enzyme-Catalyzed Oxidative C-S Bond Formation. Angewandte Chemie (International ed. in English) 15 37640689
2013 TLR and NKG2D signaling pathways mediate CS-induced pulmonary pathologies. PloS one 15 24130907
2021 Bacterial flavoprotein monooxygenase YxeK salvages toxic S-(2-succino)-adducts via oxygenolytic C-S bond cleavage. The FEBS journal 14 34510734
2022 Monitoring Noble Gases (Xe and Kr) and Aerosols (Cs and Rb) in a Molten Salt Reactor Surrogate Off-Gas Stream Using Laser-Induced Breakdown Spectroscopy (LIBS). Applied spectroscopy 13 35537200
2017 Kup-mediated Cs+ uptake and Kdp-driven K+ uptake coordinate to promote cell growth during excess Cs+ conditions in Escherichia coli. Scientific reports 13 28522840
2015 CS-SCORE: Rapid identification and removal of human genome contaminants from metagenomic datasets. Genomics 13 25944184
2009 BCR/ABL downregulates DNA-PK(CS)-dependent and upregulates backup non-homologous end joining in leukemic cells. Molecular biology reports 13 19697154
1999 Expression characteristics of CS-ACS1, CS-ACS2 and CS-ACS3, three members of the 1-aminocyclopropane-1-carboxylate synthase gene family in cucumber (Cucumis sativus L.) fruit under carbon dioxide stress. Plant & cell physiology 13 10202812
1997 Protein kinase Cs and tyrosine kinases in permissive action of prostacyclin on cerebrovascular regulation in newborn pigs. Pediatric research 13 8979294
1986 Immunogenicity of the repetitive and nonrepetitive peptide regions of the divergent CS protein of Plasmodium knowlesi. Journal of immunology (Baltimore, Md. : 1950) 13 3086454
2020 Comparison of Meconium Microbiome in Dizygotic and Monozygotic Twins Born by Caesarean Section (CS). Frontiers in microbiology 12 32582089
2007 Improved transfection efficiency of CS/DNA complex by co-transfected chitosanase gene. International journal of pharmaceutics 12 18065172
2002 Atypical protein kinase Cs are the Ras effectors that mediate repression of myogenic satellite cell differentiation. Molecular and cellular biology 12 11809805
2024 MiR-122-5p regulates erastin-induced ferroptosis via CS in nasopharyngeal carcinoma. Scientific reports 11 38693171
2024 CS proteins and ubiquitination: orchestrating DNA repair with transcription and cell division. Trends in cell biology 11 38910038
2023 Alkylcysteine Sulfoxide C-S Monooxygenase Uses a Flavin-Dependent Pummerer Rearrangement. Journal of the American Chemical Society 11 37229602
2022 Inflammasome involvement in CS-induced damage in HaCaT keratinocytes. In vitro cellular & developmental biology. Animal 11 35428946
2022 PVP/CS/Phyllanthus emblica Nanofiber Membranes for Dry Facial Masks: Manufacturing Process and Evaluations. Polymers 11 36365465
2022 A, B, C's of Trk Receptors and Their Ligands in Ocular Repair. International journal of molecular sciences 11 36430547
2019 The promotion of bone regeneration through CS/GP-CTH/antagomir-133a/b sustained release system. Nanomedicine : nanotechnology, biology, and medicine 11 31672602
1989 Mutagenicity and cytotoxicity of 2-chlorobenzylidene malonitrile (CS) and metabolites in V79 Chinese hamster cells. Archives of toxicology 11 2504130

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