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Gene Review

CS  -  citrate synthase

Sus scrofa

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Disease relevance of CS

  • To express the pig citrate synthase cDNA in Escherichia coli, we employed the inducible T7 RNA polymerase/promoter double plasmid expression vectors pGP1-2 and pT7-7 [Tabor, S., & Richardson, C. C. (1985) Proc. Natl. Acad. Sci. U.S.A. 82, 1074-1078] [1].
  • RESULTS: Relative to the control group, the exercise group demonstrated typical exercise adaptations of increased ventricular weight/body weight ratio, enhanced skeletal muscle citrate synthase activity and higher concentrations of [3H]ouabain binding sites in both skeletal and cardiac tissue (P<0.05) [2].
  • Sequence and linkage analysis of the Coxiella burnetii citrate synthase-encoding gene [3].
  • The effects of normothermia and delayed hypothermia on the levels of N-acetylaspartate (NAA), reduced glutathione (GSH) and the activities of mitochondrial complex I, II-III, IV and citrate synthase were measured in brain homogenates obtained from anaesthetized neonatal pigs following transient in vivo hypoxia-ischaemia [4].

High impact information on CS

  • The sequence of 437 amino acid residues of porcine heart citrate synthase [citrate oxaloacetate-lyase (pro-3S-CH2COO leads to acetyl-CoA), EC 4. 1. 3. 7] has been determined by the alignment of fragments generated by cleavage with cyanogen bromide and with trypsin [5].
  • This new analogue is not as good (by an order of magnitude) an inhibitor of citrate synthase [citrate oxaloacetatelyase (pro-3S-CH2-COO-vectoracetyl-CoA); EC] nor is it bound as well oleoyl-CoA [6].
  • Inhibition of citrate synthase by oleoyl-CoA: a regulatory phenomenon [6].
  • Since the only difference between these two compounds is substitution of 1,N6-ethenoadenine for the adenine of CoA, the difference in inhibition and binding implies a specific interaction between the adenine moiety of oleoyl-CoA and citrate synthase [6].
  • The polyols prevented the aggregation of CS depending on the number of hydroxyl groups in them [7].

Chemical compound and disease context of CS


Biological context of CS


Anatomical context of CS

  • Muscles exhibiting increased CS activity, however, were located primarily in the forelimb; ankle and knee extensor and respiratory muscles were unchanged with training [13].
  • The conformation of the enzyme is essentially identical with that of a previously determined "open" form of pig heart muscle citrate synthase which crystallizes in a different space group, with one monomer in the asymmetric unit, from either phosphate or citrate solution [14].
  • Many proteins, including citrate synthase, which are destined to reside in organelles such as mitochondria and chloroplasts, are the products of the nucleocytoplasmic protein synthesizing machinery and are imported post-translationally to the site of function [15].
  • Major differences were found between the hexameric citrate synthase originating from E. coli compared with those dimeric forms prepared from eukaryotic cells [11].
  • The enzyme, CS2, the sequence of which had been previously determined from its DNA, behaved differently from CS1 in its purification, kinetics, stability, and binding to the inner surface of mitochondrial inner membranes [16].

Associations of CS with chemical compounds

  • Citrate synthase is a key enzyme of the Krebs tricarboxylic acid cycle and catalyzes the stereospecific synthesis of citrate from acetyl coenzyme A and oxalacetate [1].
  • Although increasing concentrations of polyols increased protein stability in general, the refolding yields for CS decreased at higher polyol concentrations, with erythritol reducing the folding yields at all concentrations tested [7].
  • Among the various polyols used, glycerol was the most effective in enhancing the CS refolding yield, and a complete recovery of enzymatic activity was obtained at 7 m glycerol and 10 mug/ml protein, a result superior to the action of the molecular chaperones GroEL and GroES in vitro [7].
  • The co-treatment of FB(1) (CS inhibitor) with SPT inhibitors or the GlcCer synthase inhibitor had no effect on the FB(1)-induced reduction in pERK2 phosphorylation, indicating that FB(1)-mediated changes in phosphorylation of pERK2 was independent of increases in free sphinganine or its metabolites or a reduction in ceramide [17].
  • Lower CS and HAD activities were observed in the halothane sensitive pigs compared with the other pigs [18].

Other interactions of CS


Analytical, diagnostic and therapeutic context of CS

  • A 1.4 kb porcine CS cDNA probe was used to chromosomally localize the CS gene in pigs by in situ hybridization [12].
  • The presence of the CS-like, CS-A, GH-variant and, most downstream, CS-B gene was confirmed by DNA blotting and sequence analysis [23].
  • After these two steps of anion-exchange chromatography a final size-exclusion chromatography step on a Superdex 75-pg column yields CS with a purity over 99% [8].
  • A CS cDNA probe was prepared from a rabbit heart cDNA library by the polymerase chain reaction using synthetic oligonucleotide primers based on the published sequence of the porcine gene [24].
  • Using purified IgG, competitive enzyme-linked immunoassays and assays of citrate synthase activity indicate the presence of antibodies to a number of antigenic sites on the enzyme, only some of which are essential for catalytic activity [25].


  1. Isolation, nucleotide sequence, and expression of a cDNA encoding pig citrate synthase. Evans, C.T., Owens, D.D., Sumegi, B., Kispal, G., Srere, P.A. Biochemistry (1988) [Pubmed]
  2. Peripheral pre-synaptic pathway reduces the heart rate response to sympathetic activation following exercise training: role of NO. Mohan, R.M., Choate, J.K., Golding, S., Herring, N., Casadei, B., Paterson, D.J. Cardiovasc. Res. (2000) [Pubmed]
  3. Sequence and linkage analysis of the Coxiella burnetii citrate synthase-encoding gene. Heinzen, R.A., Frazier, M.E., Mallavia, L.P. Gene (1991) [Pubmed]
  4. Delayed hypothermia prevents decreases in N-acetylaspartate and reduced glutathione in the cerebral cortex of the neonatal pig following transient hypoxia-ischaemia. Brooks, K.J., Hargreaves, I., Bhakoo, K., Sellwood, M., O'Brien, F., Noone, M., Sakata, Y., Cady, E., Wylezinska, M., Thornton, J., Ordidge, R., Nguyen, Q., Clemence, M., Wyatt, J., Bates, T.E. Neurochem. Res. (2002) [Pubmed]
  5. Primary structure of porcine heart citrate synthase. Bloxham, D.P., Parmelee, D.C., Kumar, S., Wade, R.D., Ericsson, L.H., Neurath, H., Walsh, K.A., Titani, K. Proc. Natl. Acad. Sci. U.S.A. (1981) [Pubmed]
  6. Inhibition of citrate synthase by oleoyl-CoA: a regulatory phenomenon. Hsu, K.H., Powell, G.L. Proc. Natl. Acad. Sci. U.S.A. (1975) [Pubmed]
  7. Efficient refolding of aggregation-prone citrate synthase by polyol osmolytes: how well are protein folding and stability aspects coupled? Mishra, R., Seckler, R., Bhat, R. J. Biol. Chem. (2005) [Pubmed]
  8. GroE-dependent expression and purification of pig heart mitochondrial citrate synthase in Escherichia coli. Haslbeck, M., Schuster, I., Grallert, H. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. (2003) [Pubmed]
  9. Active site mutants of Escherichia coli citrate synthase. Effects of mutations on catalytic and allosteric properties. Pereira, D.S., Donald, L.J., Hosfield, D.J., Duckworth, H.W. J. Biol. Chem. (1994) [Pubmed]
  10. The effect of replacing the conserved active-site residues His-264, Asp-312 and Arg-314 on the binding and catalytic properties of Escherichia coli citrate synthase. Man, W.J., Li, Y., O'Connor, C.D., Wilton, D.C. Biochem. J. (1994) [Pubmed]
  11. Immunological mapping of fine molecular surface structures of citrate synthase enzymes from different cell types. Nemeth, P., Small, W.C., Evans, C.T., Zhi, W., Persson, L.O., Srere, P.A. J. Mol. Recognit. (1991) [Pubmed]
  12. Localization of the citrate synthase (CS) gene to the p12-p13 bands of chromosome 5 in pigs by in situ hybridization. Chaudhary, R., Chowdhary, B.P., Harbitz, I., Gustavsson, I., Evans, C.T. Hereditas (1992) [Pubmed]
  13. Skeletal muscle biochemical adaptations to exercise training in miniature swine. McAllister, R.M., Reiter, B.L., Amann, J.F., Laughlin, M.H. J. Appl. Physiol. (1997) [Pubmed]
  14. Crystal structure of an open conformation of citrate synthase from chicken heart at 2.8-A resolution. Liao, D.I., Karpusas, M., Remington, S.J. Biochemistry (1991) [Pubmed]
  15. Isolation of a cDNA encoding mitochondrial citrate synthase from Arabidopsis thaliana. Unger, E.A., Hand, J.M., Cashmore, A.R., Vasconcelos, A.C. Plant Mol. Biol. (1989) [Pubmed]
  16. Studies on yeast peroxisomal citrate synthase. Kispal, G., Srere, P.A. Arch. Biochem. Biophys. (1991) [Pubmed]
  17. Inhibition of sphingolipid biosynthesis decreases phosphorylated ERK2 in LLC-PK1 cells. Rentz, S.S., Showker, J.L., Meredith, F.I., Riley, R.T. Food Chem. Toxicol. (2005) [Pubmed]
  18. Fiber types and metabolic characteristics in muscles of wild boars, normal and halothane sensitive Swedish landrace pigs. Essén-Gustavsson, B., Lindholm, A. Comparative biochemistry and physiology. A, Comparative physiology. (1984) [Pubmed]
  19. Quantitation of the interaction between citrate synthase and malate dehydrogenase. Tompa, P., Batke, J., Ovadi, J., Welch, G.R., Srere, P.A. J. Biol. Chem. (1987) [Pubmed]
  20. Concomitant purification of three porcine heart mitochondrial enzymes: citrate synthase, aspartate aminotransferase, and malate dehydrogenase. McEvily, A.J., Flint, A.J., Harrison, J.H. Anal. Biochem. (1985) [Pubmed]
  21. Clustering of sequential enzymes in the glycolytic pathway and the citric acid cycle. Beeckmans, S., Van Driessche, E., Kanarek, L. J. Cell. Biochem. (1990) [Pubmed]
  22. Protein gamma-radiolysis in frozen solutions is a macromolecular surface phenomenon: fragmentation of lysozyme, citrate synthase and alpha-lactalbumin in native or denatured states. Audette, M., Chen, X., Houée-Levin, C., Potier, M., Le Maire, M. Int. J. Radiat. Biol. (2000) [Pubmed]
  23. Physical linkage of the human growth hormone gene family and the thyroid hormone receptor interacting protein-1 gene on chromosome 17. Surabhi, R.M., Bose, S., Kuschak, B.C., Cattini, P.A. Gene (1998) [Pubmed]
  24. Mitochondrial biogenesis in striated muscles: rapid induction of citrate synthase mRNA by nerve stimulation. Annex, B.H., Kraus, W.E., Dohm, G.L., Williams, R.S. Am. J. Physiol. (1991) [Pubmed]
  25. Citrate synthase: an immunochemical investigation of interspecies diversity. Pullen, A.M., Budgen, N., Danson, M.J., Hough, D.W. FEBS Lett. (1985) [Pubmed]
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