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Gene Review

PC  -  pyruvate carboxylase

Homo sapiens

Synonyms: PCB, Pyruvate carboxylase, mitochondrial, Pyruvic carboxylase
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Disease relevance of PC


Psychiatry related information on PC

  • Pyruvate carboxylase was markedly affected by agonal state and was very variable in Huntington's disease caudate nucleus [6].
  • A statistical analysis was performed to determine whether there were significant correlations between PCB concentrations and specific variables such as age, gender, and dietary habits [7].
  • In 9-year-old children of the Rotterdam PCB--dioxin cohort, higher prenatal PCB levels were associated with longer response times (RTs), more variation in RTs, and lower scores on the Tower of London (TOL; Shallice, 1982) [8].
  • These findings suggest that PCB/DDE exposure from Great Lakes fish has not significantly impaired hand steadiness or visual-motor coordination in this sample of older adults [9].
  • Alternative strategies for PCB risk reduction from contaminated seafood: options for children as susceptible populations [10].

High impact information on PC

  • Subcellular compartments in which folding and assembly of proteins occur seem to have a set of PCB proteins capable of mediating these and related processes, such as translocation across membranes [11].
  • Catalysis of topologically restricted folding by PCB proteins is likely to involve both an antifolding activity that postpones folding until entire domains are available and, more speculatively, a folding activity resulting from a programmed stepwise release that employs the energy of ATP hydrolysis to ensure a favorable pathway [11].
  • PCB? and melanoma [12].
  • PCB concentrations in North Atlantic surface water [13].
  • We conclude that most rats achieved hPC levels that would prevent purpura fulminans, and that hepatic gene therapy might become a viable treatment for patients with severe homozygous hPC deficiency [14].

Chemical compound and disease context of PC

  • While traumatic brain injury did not change the overall (13)C enrichment of glutamate indicating a continued oxidation of glucose, the PC/PDH ratio was reduced in the injured cortex at 3.5 h after injury [15].
  • Protocadherin-PC promotes androgen-independent prostate cancer cell growth [16].
  • Increased degrees of hypermetabolism such as severe trauma and sepsis were associated with reduction of muscle ATP and PC; AMP, free CR, lactate, and pyruvate rose [17].
  • There was a significant association between serum levels of PC III peptide and the extent of reticulin fibrosis in bone marrow biopsies [18].
  • Homozygous protein C (PC) deficiency is a rare genetic defect that usually results in fatal thrombotic complications (purpura fulminans and DIC), but it can be successfully managed with oral anticoagulants or PC replacement [19].

Biological context of PC

  • Screening both the cDNA and the gene of individuals with the simple A form of PC deficiency revealed an 1828G-->A missense mutation in 11 Ojibwa and 2 Cree patients and a 2229G-->T transversion mutation in 2 brothers of Micmac origin [20].
  • The two point mutations are located in a region of homology conserved among yeast, rat, and human PC, in the vicinity of the carboxylation domain of the enzyme [20].
  • These data provide the first characterization of the human PC gene structure, the identification of common pathogenic mutations, and the demonstration of a founder effect in the Ojibwa and Cree patients [20].
  • In mammals, PC plays a crucial role in gluconeogenesis and lipogenesis, in the biosynthesis of neurotransmitter substances, and in glucose-induced insulin secretion by pancreatic islets [1].
  • We show, through immunoblot analysis, PC enzyme activity assays, reverse-transcription PCR and mitochondrial-import experiments, that this mutation is disease-causing in the Ojibwa population owing to its decreased catalytic activity, decreased steady-state levels of expression and inefficient import into the mitochondria [21].

Anatomical context of PC

  • Thermostability studies suggested that biotin stabilizes PC and beta MCC in both cell lines [3].
  • Pharmacologic doses of biotin increase lymphocyte PCC, PC, and ACC activities [22].
  • Our data suggest that this mutation may affect the stability of the protein, resulting in decreased steady-state levels of expression, and that it may also affect the secondary structure of the protein during the import process, thereby inhibiting proper translocation into the mitochondria, where PC is active [21].
  • In both families, the probands were found to have low PC activity (range, 2-25% of control) in blood lymphocytes and skin fibroblasts associated with either diminished or normal protein levels [2].
  • In addition, PC was detected unexpectedly in delta-cells of islets [23].

Associations of PC with chemical compounds

  • PC in line 1 cells incubated with or without biotin was less stable than that in normal or line 2 cells, and the less than normal increase of enzyme activities in line 1, especially that of PC, may represent incomplete biotination [3].
  • The mutation is located in the highly conserved pyruvate-binding domain of PC [21].
  • In the first case, sequencing of patient-specific PC cDNA demonstrated a T to C substitution at nucleotide 434, which causes a valine to alanine change at amino acid residue 145 [2].
  • At the end of the clamp, dexamethasone reduced eGP and PC mRNA levels, whereas mitochondrial PEPCK mRNA levels increased [24].
  • Hence, it is possible that PC and CPS I in the centroacinar cells, intercalated duct cells, and intralobular duct cells are strongly activated and might use HCO3- ions provided by CA II and not by CA V [23].

Other interactions of PC

  • PC maps to 11q13 and distal to FRA11A, localising PC to 11q13.4-->q13.5 [25].
  • Biotin administration increased the activity of PCC, PC, and ACC in all the subjects [22].
  • Thus the analyses of them in environmental samples are difficult and furthermore complicated by interferences from other chlorinated hydrocarbons such as PCB and DDT compounds [26].
  • Glucocorticoids, glucagon and catecholamines cause an increase in PC activity or in the rate of pyruvate carboxylation in the short term [1].
  • AIM: To examine the immunohistochemical staining of endogenous biotin; of three mitochondrial biotin-binding enzymes (namely, PC, CPS I, and propionyl CoA-carboxylase); and of cytosolic acetyl CoA-carboxylase in pancreatic tissues [23].

Analytical, diagnostic and therapeutic context of PC

  • Although no high-resolution three-dimensional structure has yet been determined by X-ray crystallography, structural studies of PC have been conducted by electron microscopy, by limited proteolysis, and by cloning and sequencing of genes and cDNA encoding the enzyme [1].
  • They also showed a detectable mRNA species for PC on Northern blotting [27].
  • We have developed a variation of the solid-phase enzyme-linked immunosorbent assay (ELISA) to enable measurement of the activity and antigen levels of protein C (PC) in human plasma [28].
  • Amputations were required in 4 of 33 (12%) survivors and in 2 of 31 (6.5%) patients who received PC within 24 hours of admission into the hospital, in comparison with the predicted amputation rate of 11 of 33 (30%) [5].
  • Based on a site-directed mutagenesis approach, E229K thrombin is found to be the most optimal and potent PC activator with a marked shift in substrate specificity for PC over fibrinogen [29].


  1. Structure, function and regulation of pyruvate carboxylase. Jitrapakdee, S., Wallace, J.C. Biochem. J. (1999) [Pubmed]
  2. Molecular characterization of pyruvate carboxylase deficiency in two consanguineous families. Wexler, I.D., Kerr, D.S., Du, Y., Kaung, M.M., Stephenson, W., Lusk, M.M., Wappner, R.S., Higgins, J.J. Pediatr. Res. (1998) [Pubmed]
  3. Biochemical characterization of biotin-responsive multiple carboxylase deficiency: heterogeneity within the bio genetic complementation group. Feldman, G.L., Hsia, Y.E., Wolf, B. Am. J. Hum. Genet. (1981) [Pubmed]
  4. Pyruvate carboxylase. Wallace, J.C., Jitrapakdee, S., Chapman-Smith, A. Int. J. Biochem. Cell Biol. (1998) [Pubmed]
  5. An open-label study of the role of adjuvant hemostatic support with protein C replacement therapy in purpura fulminans-associated meningococcemia. White, B., Livingstone, W., Murphy, C., Hodgson, A., Rafferty, M., Smith, O.P. Blood (2000) [Pubmed]
  6. Changes in nine enzyme markers for neurons, glia, and endothelial cells in agonal state and Huntington's disease caudate nucleus. Butterworth, J. J. Neurochem. (1986) [Pubmed]
  7. Critical evaluation of a high-throughput analytical method for polychlorinated biphenyls in human serum: which detector for the establishment of the reference values? Turci, R., Mariani, G., Marinaccio, A., Balducci, C., Bettinelli, M., Fanelli, R., Nichetti, S., Minoia, C. Rapid Commun. Mass Spectrom. (2004) [Pubmed]
  8. Effects of perinatal exposure to PCBs on neuropsychological functions in the Rotterdam cohort at 9 years of age. Vreugdenhil, H.J., Mulder, P.G., Emmen, H.H., Weisglas-Kuperus, N. Neuropsychology. (2004) [Pubmed]
  9. Motor function in aging Great Lakes fisheaters. Schantz, S.L., Gardiner, J.C., Gasior, D.M., Sweeney, A.M., Humphrey, H.E., McCaffrey, R.J. Environmental research. (1999) [Pubmed]
  10. Alternative strategies for PCB risk reduction from contaminated seafood: options for children as susceptible populations. Judd, N.L., Griffith, W.C., Ylitalo, G.M., Faustman, E.M. Bulletin of environmental contamination and toxicology. (2002) [Pubmed]
  11. Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Rothman, J.E. Cell (1989) [Pubmed]
  12. PCB? and melanoma. Lawrence, C. N. Engl. J. Med. (1977) [Pubmed]
  13. PCB concentrations in North Atlantic surface water. Longhurst, A.R., Radford, P.J. Nature (1975) [Pubmed]
  14. Therapeutic levels of human protein C in rats after retroviral vector-mediated hepatic gene therapy. Cai, S.R., Kennedy, S.C., Bowling, W.M., Flye, M.W., Ponder, K.P. J. Clin. Invest. (1998) [Pubmed]
  15. Glucose metabolism after traumatic brain injury: estimation of pyruvate carboxylase and pyruvate dehydrogenase flux by mass isotopomer analysis. Bartnik, B.L., Hovda, D.A., Lee, P.W. J. Neurotrauma (2007) [Pubmed]
  16. Protocadherin-PC promotes androgen-independent prostate cancer cell growth. Terry, S., Queires, L., Gil-Diez-de-Medina, S., Chen, M.W., de la Taille, A., Allory, Y., Tran, P.L., Abbou, C.C., Buttyan, R., Vacherot, F. Prostate (2006) [Pubmed]
  17. Effect of injury and sepsis on high-energy phosphates in muscle and red cells. Liaw, K.Y., Askanazi, J., Michelson, C.B., Kantrowitz, L.R., Fürst, P., Kinney, J.M. The Journal of trauma. (1980) [Pubmed]
  18. Increased serum procollagen III aminoterminal peptide in myelofibrosis. Hochweiss, S., Fruchtman, S., Hahn, E.G., Gilbert, H., Donovan, P.B., Johnson, J., Goldberg, J.D., Berk, P.D. Am. J. Hematol. (1983) [Pubmed]
  19. Protein C survival during replacement therapy in homozygous protein C deficiency. Marlar, R.A., Sills, R.H., Groncy, P.K., Montgomery, R.R., Madden, R.M. Am. J. Hematol. (1992) [Pubmed]
  20. Amerindian pyruvate carboxylase deficiency is associated with two distinct missense mutations. Carbone, M.A., MacKay, N., Ling, M., Cole, D.E., Douglas, C., Rigat, B., Feigenbaum, A., Clarke, J.T., Haworth, J.C., Greenberg, C.R., Seargeant, L., Robinson, B.H. Am. J. Hum. Genet. (1998) [Pubmed]
  21. Expression and characterization of a human pyruvate carboxylase variant by retroviral gene transfer. Carbone, M.A., Robinson, B.H. Biochem. J. (2003) [Pubmed]
  22. Effects of biotin on pyruvate carboxylase, acetyl-CoA carboxylase, propionyl-CoA carboxylase, and markers for glucose and lipid homeostasis in type 2 diabetic patients and nondiabetic subjects. Báez-Saldaña, A., Zendejas-Ruiz, I., Revilla-Monsalve, C., Islas-Andrade, S., Cárdenas, A., Rojas-Ochoa, A., Vilches, A., Fernandez-Mejia, C. Am. J. Clin. Nutr. (2004) [Pubmed]
  23. Immunohistochemical localization of pyruvate carboxylase and carbamyl-phosphate synthetase I in normal and neoplastic human pancreatic tissues. Sato, T., Kashima, K., Gamachi, A., Daa, T., Nakayama, I., Yokoyama, S. Pancreas (2002) [Pubmed]
  24. Effects of colostrum feeding and glucocorticoid administration on insulin-dependent glucose metabolism in neonatal calves. Scheuer, B.H., Zbinden, Y., Schneiter, P., Tappy, L., Blum, J.W., Hammon, H.M. Domest. Anim. Endocrinol. (2006) [Pubmed]
  25. Assignment of the human pyruvate carboxylase gene (PC) to 11q13.4 by fluorescence in situ hybridisation. Walker, M.E., Baker, E., Wallace, J.C., Sutherland, G.R. Cytogenet. Cell Genet. (1995) [Pubmed]
  26. Analysis of toxaphene (PCC) and chlordane in biological samples by NCI mass spectrometry. Jansson, B., Wideqvist, U. International journal of environmental analytical chemistry. (1983) [Pubmed]
  27. The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by 3H-biotin incorporation, 35S-streptavidin labeling, and Northern blotting with a cloned cDNA probe. Robinson, B.H., Oei, J., Saudubray, J.M., Marsac, C., Bartlett, K., Quan, F., Gravel, R. Am. J. Hum. Genet. (1987) [Pubmed]
  28. Level of protein C determined by combined assays during disseminated intravascular coagulation and oral anticoagulation. Mimuro, J., Sakata, Y., Wakabayashi, K., Matsuda, M. Blood (1987) [Pubmed]
  29. Modulation of thrombin's procoagulant and anticoagulant properties. Leung, L.L., Gibbs, C.S. Thromb. Haemost. (1997) [Pubmed]
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