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Gene Review

CS  -  citrate synthase

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Disease relevance of CS

  • Epstein-Barr virus-immortalized B cell lines from six ataxia telangiectasia patients with different mutations exhibited radiation-induced CS activation, ceramide generation, and apoptosis, whereas three lines from normal patients failed to manifest these responses [1].
  • PA700 prevents the aggregation of three incompletely folded, nonubiquitinated substrates: the DeltaF-508 mutant form of cystic fibrosis transmembrane regulator, nucleotide binding domain 1, insulin B chain, and citrate synthase [2].
  • The sequences of the 16S rRNA and citrate synthase genes obtained from the two type strains were highly related to sequences of the different Bartonella species [3].
  • When expressed in terms of units gm-1, the activities of enzymes functioning in oxidative metabolism (citrate synthase, beta-hydroxybutyrylCoA dehydrogenase, and malate dehydrogenase) decrease as body weight increases [4].
  • Rickettsia africae was identified in seven (6%) of 118 patients with acute fevers of unknown etiology proven not to be malaria or typhoid fever from clinics along the coastal region of Cameroon by polymerase chain reaction (PCR) amplification and sequencing of the citrate synthase (gltA) and outer membrane protein A (ompA) genes of Rickettsia [5].

High impact information on CS

  • We demonstrate that chronic exposure of endothelial cells to NO decreased activity and protein levels of complexes I, II, and IV, whereas citrate synthase and ATP synthase were unaffected [6].
  • CS activation was obligatory, since fumonisin B1, a fungal pathogen that acts as a specific CS inhibitor, abrogated DNA damage-induced death [1].
  • EF-Tu promotes the functional folding of citrate synthase and alpha-glucosidase after urea denaturation [7].
  • However, the data suggest that the cleavage of HMG-CoA is at least partially reversible and indicate that enolization of acetyl-CoA may be dependent upon a conformational change of HMG-CoA lyase, induced by binding of acetoacetate, in a manner analogous to the keto acid dependent tritium exchange catalyzed by malate synthase and citrate synthase [8].
  • The effects of supplemental methionine (Met), supplied abomasally, on the activities of methionine synthase (MS), cystathionine synthase (CS) and betaine-homocysteine methyltransferase (BHMT) were studied in growing steers [9].

Biological context of CS

  • Furthermore, inhibition of apoptosis using the peptide caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethylketone did not affect CS activation, indicating this event is not a consequence of induction of apoptosis [1].
  • In the second experiment, the effect of omitting CS or BSA from IVM and IVM-IVF on subsequent embryo development in SOFaaci-PVA or in SOFaaci-CS was investigated [10].
  • Comparing early gestation (EG, 45-65 day) later gestation (LG, 85-110 day) and neonate (birth-1 month), specific activity of citrate synthase (CS), a Krebs cycle enzyme showed a 2 fold increase from EG to LG and a 2 fold increase from LG to neonate [11].
  • The results indicate that, at pathophysiological levels, palmitoyl CoA, a long-chain acyl CoA, is a potent inhibitor of CS and GDH with IC50 values of 3-15 microM [12].
  • Hepatic citrate synthase activity increased only in the control group after parturition [13].

Anatomical context of CS


Associations of CS with chemical compounds

  • Here we report that metabolic incorporation of 125I-labeled 5-iodo-2'deoxyuridine, which produces DNA dsb, signaled de novo ceramide synthesis by post-translational activation of ceramide synthase (CS) and apoptosis [1].
  • Fibre type composition, activities of enzymes such as citrate synthase (CS), 3-hydroxyacyl coenzyme A dehydrogenase (HAD), lactate dehydrogenase (LDH), as well as glycogen, lactate and pH levels were analysed in muscle biopsies (m. gluteus medius) obtained after bullfighting from 10 young and 10 old bulls [18].
  • Furthermore, daily CS 236 treatment after the onset of EAAU (Day 14-20) significantly reduced the severity (both clinical and histologic) of EAAU and shortened the duration of disease. iNOS inhibitor (AG) and 5-LP inhibitor (NDGA) partially attenuated EAAU [19].
  • Glutamate dehydrogenase has a higher affinity and capacity than citrate synthase for palmitoyl-CoA [20].
  • DPNH disrupts complexes with malate dehydrogenase and has little effect on those with the aminotransferase, while oxalacetate disrupts complexes with citrate synthase but has little effect on those with glutamate dehydrogenase [20].

Other interactions of CS


Analytical, diagnostic and therapeutic context of CS

  • A kinetic dissection of the unfolding pathway of CS succeeded in revealing two intermediates which form and subsequently undergo irreversible aggregation reactions [22].
  • The first group of rats received subcutaneous injection of COX 2 inhibitor CS 236 at different time points [19].


  1. Ataxia telangiectasia-mutated gene product inhibits DNA damage-induced apoptosis via ceramide synthase. Liao, W.C., Haimovitz-Friedman, A., Persaud, R.S., McLoughlin, M., Ehleiter, D., Zhang, N., Gatei, M., Lavin, M., Kolesnick, R., Fuks, Z. J. Biol. Chem. (1999) [Pubmed]
  2. Recognition of misfolding proteins by PA700, the regulatory subcomplex of the 26 S proteasome. Strickland, E., Hakala, K., Thomas, P.J., DeMartino, G.N. J. Biol. Chem. (2000) [Pubmed]
  3. Bartonella bovis Bermond et al. sp. nov. and Bartonella capreoli sp. nov., isolated from European ruminants. Bermond, D., Boulouis, H.J., Heller, R., Van Laere, G., Monteil, H., Chomel, B.B., Sander, A., Dehio, C., Piémont, Y. Int. J. Syst. Evol. Microbiol. (2002) [Pubmed]
  4. Scaling of oxidative and glycolytic enzymes in mammals. Emmett, B., Hochachka, P.W. Respiration physiology. (1981) [Pubmed]
  5. Detection of Rickettsia africae in patients and ticks along the coastal region of Cameroon. Ndip, L.M., Fokam, E.B., Bouyer, D.H., Ndip, R.N., Titanji, V.P., Walker, D.H., McBride, J.W. Am. J. Trop. Med. Hyg. (2004) [Pubmed]
  6. Chronic exposure to nitric oxide alters the free iron pool in endothelial cells: role of mitochondrial respiratory complexes and heat shock proteins. Ramachandran, A., Ceaser, E., Darley-Usmar, V.M. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  7. Chaperone properties of bacterial elongation factor EF-Tu. Caldas, T.D., El Yaagoubi, A., Richarme, G. J. Biol. Chem. (1998) [Pubmed]
  8. 3-hydroxy-3-methylglutaryl-CoA lyase: catalysis of acetyl coenzyme A enolization. Kramer, P.R., Miziorko, H.M. Biochemistry (1983) [Pubmed]
  9. Methionine supply to growing steers affects hepatic activities of methionine synthase and betaine-homocysteine methyltransferase, but not cystathionine synthase. Lambert, B.D., Titgemeyer, E.C., Stokka, G.L., DeBey, B.M., Löest, C.A. J. Nutr. (2002) [Pubmed]
  10. High bovine blastocyst development in a static in vitro production system using SOFaa medium supplemented with sodium citrate and myo-inositol with or without serum-proteins. Holm, P., Booth, P.J., Schmidt, M.H., Greve, T., Callesen, H. Theriogenology (1999) [Pubmed]
  11. Heart mitochondrial DNA and enzyme changes during early human development. Marin-Garcia, J., Ananthakrishnan, R., Goldenthal, M.J. Mol. Cell. Biochem. (2000) [Pubmed]
  12. Differential effects of fatty acyl coenzyme A derivatives on citrate synthase and glutamate dehydrogenase. Lai, J.C., Liang, B.B., Jarvi, E.J., Cooper, A.J., Lu, D.R. Res. Commun. Chem. Pathol. Pharmacol. (1993) [Pubmed]
  13. Unrestricted feed intake during the dry period impairs the postpartum oxidation and synthesis of fatty acids in the liver of dairy cows. Murondoti, A., Jorritsma, R., Beynen, A.C., Wensing, T., Geelen, M.J. J. Dairy Sci. (2004) [Pubmed]
  14. Regional distribution of citrate synthase and lactate dehydrogenase isoenzymes in the bovine heart. Sylvén, C., Lin, L., Kallner, A., Jansson, F. Acta Physiol. Scand. (1989) [Pubmed]
  15. Genetic reprogramming of lactate dehydrogenase, citrate synthase, and phosphofructokinase mRNA in bovine nuclear transfer embryos produced using bovine fibroblast cell nuclei. Winger, Q.A., Hill, J.R., Shin, T., Watson, A.J., Kraemer, D.C., Westhusin, M.E. Mol. Reprod. Dev. (2000) [Pubmed]
  16. Intracellular distribution of nicotinamide-adenine dinucleotide phosphate-linked isocitrate dehydrogenase, fumarase and citrate synthase in bovine heart muscle [proceedings]. Fatania, H.R., Dalziel, K. Biochem. Soc. Trans. (1978) [Pubmed]
  17. Intracellular distribution of NADP-linked isocitrate dehydrogenase, fumarase and citrate synthase in bovine heart muscle. Fatania, H.R., Dalziel, K. Biochim. Biophys. Acta (1980) [Pubmed]
  18. Skeletal muscle fibre characteristics in young and old bulls and metabolic response after a bullfight. Agüera, E.I., Muñoz, A., Castejón, F.M., Essén-Gustavsson, B. Journal of veterinary medicine. A, Physiology, pathology, clinical medicine. (2001) [Pubmed]
  19. Anti-inflammatory effects of specific cyclooxygenase 2,5-lipoxygenase, and inducible nitric oxide synthase inhibitors on experimental autoimmune anterior uveitis (EAAU). Bora, N.S., Sohn, J.H., Bora, P.S., Kaplan, H.J., Kulkarni, P. Ocul. Immunol. Inflamm. (2005) [Pubmed]
  20. Complexes between mitochondrial enzymes and either citrate synthase or glutamate dehydrogenase. Fahien, L.A., Kmiotek, E. Arch. Biochem. Biophys. (1983) [Pubmed]
  21. The problem of interlab variation in methods for mitochondrial disease diagnosis: enzymatic measurement of respiratory chain complexes. Gellerich, F.N., Mayr, J.A., Reuter, S., Sperl, W., Zierz, S. Mitochondrion (2004) [Pubmed]
  22. Transient interaction of Hsp90 with early unfolding intermediates of citrate synthase. Implications for heat shock in vivo. Jakob, U., Lilie, H., Meyer, I., Buchner, J. J. Biol. Chem. (1995) [Pubmed]
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