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• W2000840644 abstract "It is now more than 55 years since the mitochondrial form of phosphoenolpyruvate carboxykinase (GTP) (PEPCK 2The abbreviations used are: PEPCKphosphoenolpyruvate carboxykinasePEPCK-Mmitochondrial PEPCKPEPCK-Ccytosolic PEPCK. ; EC 4.1.1.32) from chicken liver was first reported by Utter and Kurahashi (1Utter M.F. Kurahashi K. J. Am. Chem. Soc. 1953; 75: 758Crossref Scopus (25) Google Scholar). Since that time, our understanding of the properties and biological role of this enzyme has increased greatly. We now know, for example, that there are two forms of PEPCK, one in mitochondria (PEPCK-M) and another in the cytosol (PEPCK-C), and rather than being involved exclusively in gluconeogenesis, the enzyme has a broader metabolic function in the cataplerosis of citric acid cycle intermediates (removal of citric acid cycle anions), which is required for gluconeogenesis and glyceroneogenesis. Only the metabolic role of PEPCK-C, whose transcription is acutely regulated by diet and hormones, has been studied in any detail. This is especially ironic because the genes for both isoforms are found in all eukaryotic species studied to date, and most species have considerable PEPCK-M activity in their tissues. Despite this, PEPCK-C has become a virtual marker for hepatic gluconeogenesis, and the level of its gene transcription in the liver is considered an important marker in the evaluation of type 2 diabetes. The rationale often used is that if the level of mRNA for PEPCK-C is elevated, the rate of gluconeogenesis must be increased. This may well be true for the rat and the mouse, species that have 90% PEPCK-C in their livers, but in human liver, 50% of the activity is PEPCK-M. This distribution of the PEPCK isoforms is not restricted to humans; most mammalian species studied to date have the same distribution of PEPCK (2Hanson R.W. Garber A.J. Am. J. Clin. Nutr. 1972; 25: 1010-1021Crossref PubMed Scopus (125) Google Scholar). The biology of PEPCK-M has been so poorly studied that it is not even clear if the overall activity of this enzyme can be induced by any of the factors that are known to alter the rates of hepatic gluconeogenesis. The fact that the gene for PEPCK-M is conserved throughout all eukaryotes studied to date attests to the biological importance of the enzyme, but its role in metabolism continues to be ignored. It is a causality of what may be described as the “tyranny of species.” As more and more data become available about a given species, the more that species becomes a standard for further study. The case of the mouse is a perfect example. It has become the standard for all metabolic studies not because it is the ideal animal model for metabolic analysis but rather because it can be genetically manipulated and the metabolic implications determined. An enormous amount of very valuable metabolic information has been generated over the past 25 years using the techniques of mouse genetics combined with metabolic analysis. Sadly, PEPCK-M represents only 5–10% of the total activity of PEPCK in mouse liver, so deleting the gene in that tissue is unlikely to have a relevant metabolic impact. For example, when PEPCK-C was ablated in the liver, the relatively low activity of PEPCK-M was not sufficient to maintain gluconeogenesis in that tissue (3She P. Burgess S.C. Shiota M. Flakoll P. Donahue E.P. Malloy C.R. Sherry A.D. Magnuson M.A. Diabetes. 2003; 52: 1649-1654Crossref PubMed Scopus (89) Google Scholar). Recently, Stark et al. (4Stark R. Pasquel F. Turcu A. Pongratz R.L. Roden M. Cline G.W. Shulman G.I. Kibbe R.G. J. Biol. Chem. 2009; 284: 26578-26590Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar) reported that PEPCK-M was present in β-cells isolated from mice, where it is involved in the cataplerotic recycling of citric acid cycle anions and the conversion of GTP to GDP in the mitochondria. It is thus possible that PEPCK-M is active in tissues of rodents that have not as yet been assessed. Thus, despite the fact that PEPCK-M was the first isoform of the enzyme identified 55 years ago, its biological function remains to be fully established. A review of our current knowledge of the metabolic role of both PEPCK-M and PEPCK-C is presented by Yang et al. (5Yang J. Kalhan S.C. Hanson R.W. J. Biol. Chem. 2009; 284: 27025-27029Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar) in the first of the articles in this thematic minireview series. phosphoenolpyruvate carboxykinase mitochondrial PEPCK cytosolic PEPCK. Since its discovery, the function of PEPCK has been linked virtually exclusively to gluconeogenesis despite the fact that the enzyme is present in many tissues that do not make glucose, such as brown and white adipose tissue, colon, skeletal muscle, brain, and many others (6Zimmer D.B. Magnuson M.A. J. Histochem. Cytochem. 1990; 38: 171-178Crossref PubMed Scopus (59) Google Scholar). Several alternative pathways have been suggested to explain the function of PEPCK in these tissues. One such pathway is glyceroneogenesis, which is critical for the generation of glyceride-glycerol to support the synthesis of triglyceride in a variety of mammalian tissues (7Hanson R.W. Reshef L. Biochimie. 2003; 85: 1199-1205Crossref PubMed Scopus (121) Google Scholar). However, evidence is emerging that the major function of PEPCK in all tissues is cataplerosis; this is a far broader concept upon which to base our understanding of the action of the enzyme. Cataplerosis is an important metabolic process because it is linked to citric acid cycle function and is thus central to energy metabolism. The citric acid cycle is the site of entry of the carbon skeletons of amino acids. However, the cycle does not oxidize these carbon skeletons completely to carbon dioxide, so the entry of amino acid carbon into the cycle must be accompanied by its removal, or intermediates will accumulate in the mitochondria. In a broad sense, by converting the citric acid cycle anion oxalacetate to P-enolpyruvate, PEPCK ultimately provides carbon for a number of downstream process; these include gluconeogenesis and glyceroneogenesis. Equally important, cataplerosis via PEPCK is a pathway for the generation of energy for the carbon skeletons of amino acids (8Owen O.E. Kalhan S.C. Hanson R.W. J. Biol. Chem. 2002; 277: 30409-30412Abstract Full Text Full Text PDF PubMed Scopus (776) Google Scholar) because the P-enolpyruvate produced from oxalacetate can be converted to pyruvate via pyruvate kinase and then enter the citric acid cycle as acetyl-CoA. The metabolic role of cataplerosis and the current evidence for its function are reviewed in the first minireview in this series by Yang et al. (5Yang J. Kalhan S.C. Hanson R.W. J. Biol. Chem. 2009; 284: 27025-27029Abstract Full Text Full Text PDF PubMed Scopus (183) Google Scholar). The regulation of transcription of the gene for PEPCK-C is among the most thoroughly studied of any gene, and many of the factors that control the level of this enzyme in the major tissues in which it is expressed (i.e. liver, adipose tissue, and kidney cortex) have been identified (see Ref. 10Chakravarty K. Cassuto H. Reshef L. Hanson R.W. Crit. Rev. Biochem. Mol. Biol. 2005; 40: 129-154Crossref PubMed Scopus (176) Google Scholar for a detailed review of this area). The second article in this thematic minireview series by Yang et al. (9Yang J. Reshef L. Cassuto H. Aleman G. Hanson R.W. J. Biol. Chem. 2009; 284: 27031-27035Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) reviews several aspects of the control of transcription of the gene for PEPCK-C that would benefit from more intensive research. The current trend in the area has moved away from the analysis of individual promoter function to a more global approach involving co-regulators and co-repressors that interact with specific transcription factors on the gene promoter and alter the rate of expression of the gene. Thus, co-regulators, such as PGC-1α, are viewed as “master regulator molecules,” which integrate the transcription of a broad variety of genes in response to metabolic signals, such as alterations in blood glucose. The detailed analysis of individual genes has been largely relegated to the status of “promoter bashing.” This is perhaps inevitable because gene promoters share many of the same regulatory elements and presumably respond in a similar manner to transcriptional regulators. However, making generalizations about global transcriptional control based on the response of the relatively few genes that have been studied in detail is prone to error. Much has been written on the regulation of PEPCK-C gene transcription and the factors that control its response to hormones and diet (10Chakravarty K. Cassuto H. Reshef L. Hanson R.W. Crit. Rev. Biochem. Mol. Biol. 2005; 40: 129-154Crossref PubMed Scopus (176) Google Scholar, 11Hanson R.W. Reshef L. Annu. Rev. Biochem. 1997; 66: 581-611Crossref PubMed Scopus (631) Google Scholar, 12Granner D.K. O'Brien R.M. Diabetes Care. 1992; 15: 369-395Crossref PubMed Scopus (130) Google Scholar). In the second minireview in this series by Yang et al. (9Yang J. Reshef L. Cassuto H. Aleman G. Hanson R.W. J. Biol. Chem. 2009; 284: 27031-27035Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), the emphasis is on the potential role of chromatin remodeling in the transcription of the gene and the potential insights that may be gained from a critical analysis of the genome-wide sequence of the PEPCK-C gene promoter. The degree of sequence conservation in eukaryotes of the first 500 bp 5′ of the start site of gene transcription in the PEPCK-C gene promoter is striking. In addition, the conservation of sequences in the gene promoter provides a new insight into putative regulatory elements that were not recognized previously. For example, there is a hitherto unrecognized Sp1 site within the cAMP regulatory element of the gene promoter, a region that is required for the transcriptional response of the gene to cAMP. How and if Sp1 interacts with members of the CAAT/enhancer-binding protein family of transcription factors that bind at the cAMP regulatory element are not clear. Renal gene transcription requires the HNF-1-binding site (13Patel Y.M. Yun J.S. Liu J. McGrane M.M. Hanson R.W. J. Biol. Chem. 1994; 269: 5619-5628Abstract Full Text PDF PubMed Google Scholar, 14Curthoys N.P. Gstraunthaler G. Am. J. Physiol. Renal Physiol. 2001; 281: F381-F390Crossref PubMed Google Scholar), which is present at −200 to −164 bp in the PEPCK-C gene promoter (15Roesler W.J. Vandenbark G.R. Hanson R.W. J. Biol. Chem. 1989; 264: 9657-9664Abstract Full Text PDF PubMed Google Scholar). However, from the genome-wide analysis of promoter sequences, it is apparent that all mammalian species studied have two highly conserved HNF-1-binding sites. The role of these individual sites has not been studied. Finally, there is a common assumption in studies of the control of gene transcription that a gene promoter from one species is an appropriate model for understanding this process in related mammalian species. However, a close analysis of the PEPCK-C gene promoter indicates that the SREBP-1-binding site varies in number and position depending upon the species. This transcription factor stimulates the expression of genes involved in lipid synthesis and was also shown to inhibit transcription of the gene for PEPCK-C in hepatoma cells (16Chakravarty K. Leahy P. Becard D. Hakimi P. Foretz M. Ferre P. Foufelle F. Hanson R.W. J. Biol. Chem. 2001; 276: 34816-34823Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 17Chakravarty K. Wu S.Y. Chiang C.M. Samols D. Hanson R.W. J. Biol. Chem. 2004; 279: 15385-15395Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). There are several lines of evidence, some from older literature and others more recent, that support an important role of acetylation of histones and of specific transcription factors in the regulation of PEPCK-C gene transcription (18Benvenisty N. Mencher D. Meyuhas O. Razin A. Reshef L. Proc. Natl. Acad. Sci. U.S.A. 1985; 82: 267-271Crossref PubMed Scopus (71) Google Scholar, 19Benvenisty N. Reshef L. Proc. Natl. Acad. Sci. U.S.A. 1987; 84: 1132-1136Crossref PubMed Scopus (28) Google Scholar, 20Ip Y.T. Fournier R.E. Chalkley R. Mol. Cell. Biol. 1990; 10: 3782-3787Crossref PubMed Scopus (14) Google Scholar, 21Cissell M.A. Chalkley R. Biochim. Biophys. Acta. 1999; 1445: 299-313Crossref PubMed Scopus (5) Google Scholar, 22Hall R.K. Wang X.L. George L. Koch S.R. Granner D.K. Mol. Endocrinol. 2007; 21: 550-563Crossref PubMed Scopus (60) Google Scholar). In the second minireview in this series (9Yang J. Reshef L. Cassuto H. Aleman G. Hanson R.W. J. Biol. Chem. 2009; 284: 27031-27035Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar), we highlight a number of studies that implicate alterations in histone modification as a key factor in the development and regulation of PEPCK-C gene transcription. The catalytic mechanism of both isoforms of PEPCK has been studied in detail since the enzyme was first isolated. These studies resulted in different amino acids being potentially implicated as being involved in catalysis (23Makinen A.L. Nowak T. J. Biol. Chem. 1989; 264: 12148-12157Abstract Full Text PDF PubMed Google Scholar, 24Lewis C.T. Haley B.E. Carlson G.M. Biochemistry. 1989; 28: 9248-9255Crossref PubMed Scopus (24) Google Scholar, 25Ash D.E. Emig F.A. Chowdhury S.A. Satoh Y. Schramm V.L. J. Biol. Chem. 1990; 265: 7377-7384Abstract Full Text PDF PubMed Google Scholar, 26Lewis C.T. Seyer J.M. Cassell R.G. Carlson G.M. J. Biol. Chem. 1993; 268: 1628-1636Abstract Full Text PDF PubMed Google Scholar, 27Krautwurst H. Bazaes S. González F.D. Jabalquinto A.M. Frey P.A. Cardemil E. Biochemistry. 1998; 37: 6295-6302Crossref PubMed Scopus (49) Google Scholar). A giant step toward the development of a unifying mechanism of PEPCK catalysis, invoking potential roles for specific amino acids, came with the determination of the high-resolution crystal structures of the enzymes from Escherichia coli in 1996 (28Matte A. Goldie H. Sweet R.M. Delbaere L.T. J. Mol. Biol. 1996; 256: 126-143Crossref PubMed Scopus (94) Google Scholar) and of PEPCK-C from human liver in 2002 (29Dunten P. Belunis C. Crowther R. Hollfelder K. Kammlott U. Levin W. Michel H. Ramsey G.B. Swain A. Weber D. Wertheimer S.J. J. Mol. Biol. 2002; 316: 257-264Crossref PubMed Scopus (65) Google Scholar). Building upon the previous body of biochemical data, these structural studies painted a clearer picture of the unique active-site design that allows PEPCK to juxtapose the anionic substrates of the reaction and stabilize the increasing negative charge that develops upon formation of the transition states of the reaction. Complementing the earlier work on PEPCK, more recent structural studies on the mitochondrial and cytosolic isozymes from chicken and rat, respectively (30Holyoak T. Sullivan S.M. Nowak T. Biochemistry. 2006; 45: 8254-8263Crossref PubMed Scopus (61) Google Scholar, 31Sullivan S.M. Holyoak T. Biochemistry. 2007; 46: 10078-10088Crossref PubMed Scopus (45) Google Scholar, 32Sullivan S.M. Holyoak T. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13829-13834Crossref PubMed Scopus (128) Google Scholar), indicate the importance of conformational change in the mechanism of PEPCK catalysis. It is notable, for example, that the active site of both the GTP- and ATP-linked forms of PEPCK is capped by a mobile Ω-loop lid domain, whose closure is critical for catalysis (32Sullivan S.M. Holyoak T. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13829-13834Crossref PubMed Scopus (128) Google Scholar). The importance of conformational change at the active site is further illustrated by the necessity for movement of the nucleotide P-loop motif during the catalytic cycle. The dynamic nature of this loop domain provides a mechanistic basis for the long-standing observation that GTP-utilizing isozymes of PEPCK are inactivated by the modification of Cys-288 (23Makinen A.L. Nowak T. J. Biol. Chem. 1989; 264: 12148-12157Abstract Full Text PDF PubMed Google Scholar), which is found to reside in this loop. Inspection of the structural data on PEPCK also suggests an explanation for the nucleotide specificity that is a distinguishing feature between the enzyme from vertebrates, which use GTP as a phosphoryl donor, and the enzymes from yeast and E. coli, which use ATP. The minireview by Carlson and Holyoak (33Carlson G.M. Holyoak T. J. Biol. Chem. 2009; 284: 27037-27041Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar) provides fascinating insight into the reaction mechanism of PEPCK, the details of which have been surprisingly elusive over the years since the discovery of the enzyme." @default.
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• W2000840644 title "Thematic Minireview Series: A Perspective on the Biology of Phosphoenolpyruvate Carboxykinase 55 Years After Its Discovery" @default.
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