Phosphoenolpyruvate carboxykinase

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Not to be confused with Phosphoenolpyruvate carboxylase.
Phosphoenolpyruvate carboxykinase
PBB Protein PCK1 image.jpg
PDB rendering based on 1khb.
Symbol PEPCK
Pfam PF00821
InterPro IPR008209
SCOP 1khf
phosphoenolpyruvate carboxykinase 1 (soluble)
Symbol PCK1
Alt. symbols PEPCK-C
Entrez 5105
HUGO 8724
OMIM 261680
RefSeq NM_002591
Other data
EC number
Locus Chr. 20 q13.31
phosphoenolpyruvate carboxykinase 2 (mitochondrial)
Symbol PCK2
Alt. symbols PEPCK-M, PEPCK2
Entrez 5106
HUGO 8725
OMIM 261650
RefSeq NM_001018073
Other data
EC number
Locus Chr. 14 q12


It is found in two forms, cytosolic and mitochondrial.

PEPCK in different species[edit]















In leaves, 5% CO2 content in the atmosphere leads to higher PEPCK abundance.[7]



PEPCK of Mycobacterium tuberculosis has been shown to trigger the immune system in mice by increasing cytokine activity.[9]


Function in gluconeogenesis[edit]

It has been shown that PEPCK-C catalyzes the rate-controlling step of gluconeogenesis, the process whereby glucose is synthesized. The enzyme has therefore been thought to be essential in glucose homeostasis, as evidenced by laboratory mice that contracted diabetes mellitus type 2 as a result of the overexpression of PEPCK-C.[10]

A recent study suggests that the role that PEPCK-C plays in gluconeogenesis may be mediated by the citric acid cycle, the activity of which was found to be directly related to PEPCK-C abundance.[11]

PEPCK-C levels alone were not found to be highly correlated with gluconeogenesis in the mouse liver, as previous studies have suggested.[11] While the mouse liver almost exclusively expresses PEPCK-C, humans equally present a mitochondrial isozyme (PEPCK-M). PEPCK-M has gluconeogenic potential per se.[12] Therefore, the role of PEPCK-C and PEPCK-M in gluconeogenesis may be more complex and involve more factors than was previously believed.

PEPCK activity in Cancer[edit]

PEPCK has not been considered in cancer research until recently. It has been shown that in human tumor samples and human cancer cell lines (breast, colon and lung cancer cells) PEPCK-M, and not PEPCK-C, was expressed at enough levels to play a relevant metabolic role.[13][14] Therefore, PEPCK-M could have a role in cancer cells, especially under nutrient limitation or other stress conditions.






Reaction Pathway[edit]

PEPCase converts oxaloacetate into phosphoenolpyruvate and carbon dioxide.


In fermentation, PEPCK catalyzes the reaction of PEP and carbon dioxide to OAA, and ADP is therefore converted to ATP with the addition of a phosphate group.[18]


In humans[edit]

PEPCK-C is enhanced, both in terms of its production and activation, by many factors. Transcription of the PEPCK-C gene is stimulated by glucagon, glucocorticoids, retinoic acid, and adenosine 3’,5’-monophosphate (cAMP), while it is inhibited by insulin.[19] Of these factors, insulin, a hormone that is deficient in the case of diabetes, is considered dominant, as it inhibits the transcription of many of the stimulatory elements.[19] PEPCK activity is also inhibited by hydrazine sulfate, and the inhibition therefore decreases the rate of gluconeogenesis.[20]


The GTP-specific activity of PEPCK is highest when Mn2+ and Mg2+ are available.[8] In addition, hyper-reactive cysteine (C307) is involved in the binding of Mn2+ to the active site.[15]






  1. ^ Trapani S, Linss J, Goldenberg S, Fischer H, Craievich AF, Oliva G (November 2001). "Crystal structure of the dimeric phosphoenolpyruvate carboxykinase (PEPCK) from Trypanosoma cruzi at 2 A resolution". Journal of Molecular Biology 313 (5): 1059–72. doi:10.1006/jmbi.2001.5093. PMID 11700062. 
  2. ^ Chakravarty K, Cassuto H, Reshef L, Hanson RW (2005). "Factors that control the tissue-specific transcription of the gene for phosphoenolpyruvate carboxykinase-C". Critical reviews in biochemistry and molecular biology 40 (3): 129–54. doi:10.1080/10409230590935479. PMID 15917397. 
  3. ^ Nash JT , Szabo DT, Carey GB (2012). "Polybrominated diphenyl ethers alter hepatic phosphoenolpyruvate carboxykinase enzyme kinetics in male Wistar rats: implications for lipid and glucose metabolism.". Journal of Toxicological and Environmental Health Part A 76 (2): 142–56. doi:10.1080/15287394.2012.738457. 
  4. ^ Kanai R, Edwards, GE (1999). "3. The Biochemistry of C4 Photosynthesis". In Sage RF, Monson RK. C4 Plant Biology. pp. 43–87. ISBN 0-12-614440-0. 
  5. ^ Christopher JT, Holtum JAM (1996). "Patterns of carbon partitioning in leaves of Crassulacean acid metabolism species during deacidification". Plant Physiol. 112 (1): 393–399. doi:10.1104/pp.112.1.393. PMC 157961. PMID 12226397. 
  6. ^ Voznesenskaya E.V., Franceschi V.R., Chuong S.D., Edwards G.E. (2006). "Functional characterization of phosphoenolpyruvate carboxykinase-type C4 leaf anatomy: immuno-cytochemical and ultrastructural analyses". Annals of Botany 98 (1): 77–91. doi:10.1093/aob/mcl096. 
  7. ^ a b c d Chen ZH, Walker RP, Técsi LI, Lea PJ, Leegood RC (May 2004). "Phosphoenolpyruvate carboxykinase in cucumber plants is increased both by ammonium and by acidification, and is present in the phloem". Planta 219 (1): 48–58. doi:10.1007/s00425-004-1220-y. PMID 14991407. 
  8. ^ a b Aich S, Imabayashi F, Delbaere LT (October 2003). "Expression, purification, and characterization of a bacterial GTP-dependent PEP carboxykinase". Protein expression and purification 31 (2): 298–304. doi:10.1016/S1046-5928(03)00189-X. PMID 14550651. 
  9. ^ a b Liu K, Ba X, Yu J, Li J, Wei Q, Han G, Li G, Cui Y. (August 2006). "The phosphoenolpyruvate carboxykinase of Mycobacterium tuberculosis induces strong cell-mediated immune responses in mice". Molecular and cellular biochemistry 288 (1-2): 65–71. doi:10.1007/s11010-006-9119-5. PMID 16691317. 
  11. ^ a b Burgess SC, He T, Yan Z, Lindner J, Sherry AD, Malloy CR, Browning JD, Magnuson MA (April 2007). "Cytosolic phosphoenolpyruvate carboxykinase does not solely control the rate of hepatic gluconeogenesis in the intact mouse liver". Cell metabolism 5 (4): 313–20. doi:10.1016/j.cmet.2007.03.004. PMC 2680089. PMID 17403375. 
  12. ^ Méndez-Lucas A, Duarte JA, Sunny NE, et al. (July 2013). "PEPCK-M expression in mouse liver potentiates, not replaces, PEPCK-C mediated gluconeogenesis". J. Hepatol. 59 (1): 105–13. doi:10.1016/j.jhep.2013.02.020. PMC 3910155. PMID 23466304. 
  13. ^ Méndez-Lucas A, Hyroššová P, Novellasdemunt L, Viñals F, Perales JC (August 2014). "Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M) is a pro-survival, endoplasmic reticulum (ER) stress response gene involved in tumor cell adaptation to nutrient availability". J. Biol. Chem. 289 (32): 22090–102. doi:10.1074/jbc.M114.566927. PMID 24973213. 
  14. ^ Leithner K, Hrzenjak A, Trötzmüller M, et al. (March 2014). "PCK2 activation mediates an adaptive response to glucose depletion in lung cancer". Oncogene. doi:10.1038/onc.2014.47. PMID 24632615. 
  15. ^ a b c Holyoak T, Sullivan SM, Nowak T (July 2006). "Structural insights into the mechanism of PEPCK catalysis". Biochemistry 45 (27): 8254–63. doi:10.1021/bi060269g. PMID 16819824. 
  16. ^ a b c Delbaere LT, Sudom AM, Prasad L, Leduc Y, Goldie H (March 2004). "Structure/function studies of phosphoryl transfer by phosphoenolpyruvate carboxykinase". Biochimica et Biophysica Acta 1697 (1-2): 271–8. doi:10.1016/j.bbapap.2003.11.030. PMID 15023367. 
  17. ^ a b Zamboni N, Maaheimo H, Szyperski T, Hohmann HP, Sauer U (October 2004). "The phosphoenolpyruvate carboxykinase also catalyzes C3 carboxylation at the interface of glycolysis and the TCA cycle of Bacillus subtilis". Metabolic engineering 6 (4): 277–84. doi:10.1016/j.ymben.2004.03.001. PMID 15491857. 
  18. ^ Chao YP, Liao JC (February 1994). "Metabolic responses to substrate futile cycling in Escherichia coli". The Journal of Biological Chemistry 269 (7): 5122–6. PMID 8106492. 
  19. ^ a b O'Brien RM, Lucas PC, Forest CD, Magnuson MA, Granner DK (August 1990). "Identification of a sequence in the PEPCK-C gene that mediates a negative effect of insulin on transcription". Science 249 (4968): 533–7. doi:10.1126/science.2166335. PMID 2166335. 
  20. ^ Mazzio E, Soliman KF (January 2003). "The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity". Neurotoxicology 24 (1): 137–47. doi:10.1016/S0161-813X(02)00110-9. PMID 12564389. 

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