Disease relevance of PEPCK-M

• We have previously shown the gene coding for the mitochondrial form of PEPCK (PEPCK-M) segregates for markers that are collected with resistance to Marek's disease [1].
• These differences are likely to be genetic, as hormonal treatment of a chicken hepatoma cell line indicates that whereas the mRNA levels for PEPCK-C are hormonally regulated, the expression of PEPCK-M mRNA is unresponsive [2].
• Birds given injections of UV-inactivated RE viruses or reticuloendotheliosis virus-transformed, non-virus-producing tumor cells also exhibited a reduction in phosphoenolpyruvate carboxykinase activity [3].
• Inhibition of hepatic phosphoenolpyruvate carboxykinase by avian reticuloendotheliosis viruses [3].
• The gene for cytosolic phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) from the chicken was isolated from a recombinant library containing the chicken genome in phage lambda Charon 4A [4].

High impact information on PEPCK-M

• Nucleotide sequence of the mRNA encoding the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) from the chicken [5].
• Conserved regions of the enzyme, that may interact with substrates, were identified by comparing the amino acid sequence of phosphoenolpyruvate carboxykinase with that of other proteins that use guanine nucleotides and phosphoenolpyruvate as substrates [5].
• Peroxisome proliferator-activated receptor gamma and chicken ovalbumin upstream promoter transcription factor II negatively regulate the phosphoenolpyruvate carboxykinase promoter via a common element [6].
• The gene encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is a PPARgamma/RXR target gene in adipose tissue [6].
• In transiently transfected fibroblasts COUP-TFII acts at gAF1/PCK1 to inhibit PPARgamma/RXR activation via PCK2 [6].

Biological context of PEPCK-M

• The amino acid sequence of the mitochondrial form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-M) from the chicken was deduced from the 3571 nucleotide sequence of three overlapping cDNA clones [7].
• Gluconeogenesis in the chicken has unique features due in part to the presence of two isozymes of PEPCK, a cytosolic form, PEPCK-C, and a mitochondrial form, PEPCK-M, which have novel patterns of expression [2].
• In addition, significant genotypic disequilibria were observed between two of the three alleles of PEPCK-C and between one of these alleles and the two RFLP alleles of PEPCK-M [8].
• There was significant interaction between PEPCK-C genotypes and mitochondrial PEPCK (PEPCK-M) genotypes defined by a single RFLP [8].
• The experiments reported herein suggest that inhibition by 3-MP is due to specific and reversible binding within the active site of phosphoenolpyruvate carboxykinase [9].

Anatomical context of PEPCK-M

• Previous work from our laboratory (Watford, M., Hod, Y., Chiao, Y. B., Utter M. F., and Hanson R. W. (1981) J. Biol. Chem. 256, 10023-10027) indicated that in the chicken, hepatic phosphoenolpyruvate carboxykinase is in the mitochondria, whereas kidney contains both a mitochondrial and cytosolic form of the enzyme [10].
• The purification, characterization, and activation of phosphoenolpyruvate carboxykinase from chicken liver mitochondria [11].
• Development regulation of basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in chick embryo liver in vivo [12].
• On the nature of three forms of phosphoenolpyruvate carboxykinase occurring in the cytosol of chicken liver [13].
• Control of gluconeogenesis in chick (Gallus domesticus) isolated hepatocytes: effect of redox state and phosphoenolpyruvate carboxykinase (EC 4.1.1.32) location [14].

Associations of PEPCK-M with chemical compounds

• The gene coding for the mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M), a pivotal component in gluconeogenesis from lactate via the Cori cycle, was highly polymorphic in strains of egg-type chickens (White Leghorn) of different origins [15].
• When the extramitochondrial [ATP]/[ADP] was greater than the intramitochondrial [ATPfree]/[ADPfree] calculated from the phosphoenolpyruvate carboxykinase reaction, there was net synthesis of phosphoenolpyruvate, but when it was less, there was net disappearance of phosphoenolpyruvate [16].
• The activation of the avian liver phosphoenolpyruvate carboxykinase catalyzed reversible decarboxylation of oxalacetate by Mn2+ has been studied [17].
• Substrate protection studies indicate an arginine residue(s) at the CO2 site of phosphoenolpyruvate carboxykinase [18].
• Labeling of phosphoenolpyruvate carboxykinase in the absence of CO2 yielded 6 mol of label/enzyme [18].

Other interactions of PEPCK-M

• Thus, PEPCK-M and PEPCK-C, clearly represented the products of two distinct genes, which were distinguished by altered protein sequences and non-cross-hybridizing, differentially regulated mRNAs [7].
• Transcription activation by the orphan nuclear receptor, chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI). Definition of the domain involved in the glucocorticoid response of the phosphoenolpyruvate carboxykinase gene [19].
• Administration of glucagon, epinephrine, or dibutyryl cAMP to chicks induced cytosol-specific phosphoenolpyruvate carboxykinase in liver [20].

Analytical, diagnostic and therapeutic context of PEPCK-M

• Circular dichroism studies show little change in secondary structure of pyridoxal 5'-phosphate modified phosphoenolpyruvate carboxykinase [21].
• Phosphoenolpyruvate carboxykinase of chicken liver cytosol was purified to homogeneity by procedures including affinity chromatography with GTP as a ligand [22].
• The effects of the DNA cross-linking agent and chemotherapy drug, mitomycin C (MMC), on expression of the developmental and hormone-regulated gene, phosphoenolpyruvate carboxykinase (PEPCK), were examined in chick embryo liver in vivo as a function of development and were compared with changes in the chromatin structure of the PEPCK gene promoter [23].

References