The Experts below are selected from a list of 6462 Experts worldwide ranked by ideXlab platform
Richard W Hanson - One of the best experts on this subject based on the ideXlab platform.
-
what is the metabolic role of Phosphoenolpyruvate Carboxykinase
Journal of Biological Chemistry, 2009Co-Authors: Jianqi Yang, Richard W Hanson, Satish C KalhanAbstract:The enzyme Phosphoenolpyruvate Carboxykinase (GTP; EC 4.1.1.32) (PEPCK)2 has the unusual distinction of being very well studied but metabolically misunderstood. As we will document in this minireview, the enzyme has been almost exclusively linked to gluconeogenesis to the point that changes in the levels of PEPCK mRNA or its activity are associated with the control of hepatic glucose output and, more recently, with alterations in life span. That a tissue such as brown adipose tissue, which does not make glucose, has more PEPCK activity on a protein basis than is present in the liver is largely ignored. In addition, all eukaryotes have a gene for both a mitochondrial (PEPCK-M) and cytosolic (PEPCK-C) form of the enzyme. In the livers of most mammals studied to date (including humans), 50% of the total PEPCK activity is PEPCK-M. However, for reasons to be discussed, only PEPCK-C has been studied in any detail in mammals. Thus, the “strange case of PEPCK-M” deserves our attention. This minireview is an attempt to broaden our prospective on the metabolic role of this enzyme by reviewing the body of literature that has accumulated demonstrating that PEPCK plays a key role in a several metabolic processes associated with cataplerosis.
-
REGULATION OF Phosphoenolpyruvate Carboxykinase (GTP) GENE EXPRESSION
Annual review of biochemistry, 1997Co-Authors: Richard W Hanson, Lea ReshefAbstract:Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating the key role played at these sites by the isoforms of CAAT/enhancer binding protein in patterning of PEPCK-C gene expression during the perinatal period. The PEPCK-C gene provides a model for the metabolic control of gene transcription.
-
regulation of Phosphoenolpyruvate Carboxykinase gtp gene expression
Annual Review of Biochemistry, 1997Co-Authors: Richard W Hanson, Lea ReshefAbstract:▪ Abstract Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating...
Lea Reshef - One of the best experts on this subject based on the ideXlab platform.
-
REGULATION OF Phosphoenolpyruvate Carboxykinase (GTP) GENE EXPRESSION
Annual review of biochemistry, 1997Co-Authors: Richard W Hanson, Lea ReshefAbstract:Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating the key role played at these sites by the isoforms of CAAT/enhancer binding protein in patterning of PEPCK-C gene expression during the perinatal period. The PEPCK-C gene provides a model for the metabolic control of gene transcription.
-
regulation of Phosphoenolpyruvate Carboxykinase gtp gene expression
Annual Review of Biochemistry, 1997Co-Authors: Richard W Hanson, Lea ReshefAbstract:▪ Abstract Phosphoenolpyruvate Carboxykinase (GTP) (EC 4.1.1.32) (PEPCK) is a key enzyme in the synthesis of glucose in the liver and kidney and of glyceride-glycerol in white adipose tissue and the small intestine. The gene for the cytosolic form of PEPCK (PEPCK-C) is acutely regulated by a variety of dietary and hormonal signals, which result in alteration of synthesis of the enzyme. Major factors that increase PEPCK-C gene expression include cyclic AMP, glucocorticoids, and thyroid hormone, whereas insulin inhibits this process. PEPCK-C is absent in fetal liver but appears at birth, concomitant with the capacity for gluconeogenesis. Regulatory elements that control transcription of the PEPCK-C gene in liver, kidney, and adipose tissue have been delineated, and many of the transcription factors that bind to these elements have been identified. Transgenic mice have been especially useful in elucidating the physiological roles of specific sequence elements in the PEPCK-C gene promoter and in demonstrating...
Alberto A Iglesias - One of the best experts on this subject based on the ideXlab platform.
-
proteolytic cleavage of arabidopsis thaliana Phosphoenolpyruvate Carboxykinase 1 modifies its allosteric regulation
Journal of Experimental Botany, 2021Co-Authors: Bruno E Rojas, Matias Daniel Hartman, Carlos Maria Figueroa, Alberto A IglesiasAbstract:Phosphoenolpyruvate Carboxykinase (PEPCK) plays a crucial role in gluconeogenesis. In this work, we analyze the proteolysis of Arabidopsis thaliana PEPCK1 (AthPEPCK1) in germinating seedlings. We found that the amount of AthPEPCK1 protein peaks at 24-48 h post-imbibition. Concomitantly, we observed shorter versions of AthPEPCK1, putatively generated by metacaspase-9 (AthMC9). To study the impact of AthMC9 cleavage on the kinetic and regulatory properties of AthPEPCK1, we produced truncated mutants based on the reported AthMC9 cleavage sites. The Δ19 and Δ101 truncated mutants of AthPEPCK1 showed similar kinetic parameters and the same quaternary structure as the wild type. However, activation by malate and inhibition by glucose 6-phosphate were abolished in the Δ101 mutant. We propose that proteolysis of AthPEPCK1 in germinating seedlings operates as a mechanism to adapt the sensitivity to allosteric regulation during the sink-to-source transition.
-
proteolytic cleavage of arabidopsis thaliana Phosphoenolpyruvate Carboxykinase 1 modifies its allosteric regulation
bioRxiv, 2020Co-Authors: Bruno E Rojas, Matias Daniel Hartman, Carlos Maria Figueroa, Alberto A IglesiasAbstract:Phosphoenolpyruvate Carboxykinase (PEPCK) plays a crucial role in gluconeogenesis. In this work, we analyze the proteolysis of Arabidopsis thaliana PEPCK1 (AthPEPCK1) in germinating seedlings. We found that expression of AthPEPCK1 peaks at 24-48 hours post-imbibition. Concomitantly, we observed shorter versions of AthPEPCK1, putatively generated by metacaspase-9 (AthMC9). To study the impact of AthMC9 cleavage on the kinetic and regulatory properties of AthPEPCK1, we produced truncated mutants based on the reported AthMC9 cleavage sites. The {Delta}19 and {Delta}101 truncated mutants of AthPEPCK1 showed similar kinetic parameters and the same quaternary structure than the WT. However, activation by malate and inhibition by glucose 6-phosphate were abolished in the {Delta}101 mutant. We propose that proteolysis of AthPEPCK1 in germinating seedlings operates as a mechanism to adapt the sensitivity to allosteric regulation during the sink-to-source transition. HighlightThis paper describes the effects of the N-terminal proteolytic cleavage on the kinetic and regulatory properties of Arabidopsis thaliana Phosphoenolpyruvate Carboxykinase-1.
R W Hanson - One of the best experts on this subject based on the ideXlab platform.
-
Regulation of Phosphoenolpyruvate Carboxykinase (GTP) gene transcription.
Molecular and cellular biochemistry, 1991Co-Authors: R W HansonAbstract:Transcription of the gene for Phosphoenolpyruvate Carboxykinase is regulated by several hormones which control the level of glucose synthesis in vertebrate animals. A 490 bp segment located at the 5' end of the structural gene contains the necessary regulatory elements to account for the pattern of transcriptional regulation characteristic of the Phosphoenolpyruvate Carboxykinase gene. Multiple cis binding sites within the promoter and nuclear binding proteins have been identified and shown to play a role in the regulation of gene transcription. The interaction of these transcription factors with each other and with the Phosphoenolpyruvate Carboxykinase promoter is central to the regulated expression of this gene. The key role of cAMP and insulin in controlling the level of gene transcription will be discussed and related to the function of transcription factors currently known to regulate the tissue specific expression of the Phosphoenolpyruvate Carboxykinase gene.
Daryl K Granner - One of the best experts on this subject based on the ideXlab platform.
-
estrogen related receptor α is a repressor of Phosphoenolpyruvate Carboxykinase gene transcription
Journal of Biological Chemistry, 2006Co-Authors: Birger Herzog, Vincent Giguère, Jessica Cardenas, Robert K Hall, Josep A Villena, Philip J Budge, Daryl K Granner, Anastasia KralliAbstract:Abstract The orphan nuclear receptor estrogen-related receptor (ERR) α is a downstream effector of the transcriptional coactivator PGC-1α in the regulation of genes important for mitochondrial oxidative capacity. PGC-1α is also a potent activator of the transcriptional program required for hepatic gluconeogenesis, and in particular of the key gluconeogenic enzyme Phosphoenolpyruvate Carboxykinase (PEPCK). We report here that the regulatory sequences of the PEPCK gene harbor a functional ERRα binding site. However, in contrast to the co-stimulating effects of ERRα and PGC-1α on mitochondrial gene expression, ERRα acts as a transcriptional repressor of the PEPCK gene. Suppression of ERRα expression by small interfering RNA leads to reduced binding of ERRα to the endogenous PEPCK gene, and an increase in promoter occupancy by PGC-1α, suggesting that part of the ERRα function at this gene is to antagonize the action of PGC-1α. In agreement with the in vitro studies, animals that lack ERRα show increased expression of gluconeogenic genes, including PEPCK and glycerol kinase, but decreased expression of mitochondrial genes, such as ATP synthase subunit β and cytochrome c-1. Our findings suggest that ERRα has opposing effects on genes important for mitochondrial oxidative capacity and gluconeogenesis. The different functions of ERRα in the regulation of these pathways suggest that enhancing ERRα activity could have beneficial effects on glucose metabolism in diabetic subjects by two distinct mechanisms: increasing mitochondrial oxidative capacity in peripheral tissues and liver, and suppressing hepatic glucose production.
-
accessory factors facilitate the binding of glucocorticoid receptor to the Phosphoenolpyruvate Carboxykinase gene promoter
Journal of Biological Chemistry, 2001Co-Authors: John M Stafford, John C Wilkinson, Joseph M Beechem, Daryl K GrannerAbstract:Abstract Glucocorticoid induction of the Phosphoenolpyruvate Carboxykinase (PEPCK) gene requires a glucocorticoid response unit (GRU) comprised of two non-consensus glucocorticoid receptor (GR) binding sites, GR1 and GR2, and at least three accessory factor elements (gAF1–3). DNA-binding accessory proteins are commonly required for the regulation of genes whose products play an important role in metabolism, development, and a variety of defense responses, but little is known about why they are necessary. Quantitative, real time homogenous assays of cooperative protein-DNA interactions in complex media (e.g. nuclear extracts) have not previously been reported. Here we perform quantitative, real time equilibrium and stopped-flow fluorescence anisotropy measurements of protein-DNA interactions in nuclear extracts to demonstrate that GR binds to the GR1-GR2 elements poorly as compared with a palindromic or consensus glucocorticoid response element (GRE). Inclusion of either the gAF1 or gAF2 element with GR1-GR2, however, creates a high affinity binding environment for GR. GR can undergo multiple rounds of binding and dissociation to the palindromic GRE in less than 100 ms at nanomolar concentrations. The dissociation rate of GR is differentially slowed by the gAF1 or gAF2 elements that bind two functionally distinct accessory factors, COUP-TF/HNF4 and HNF3, respectively.
-
ISOLATION AND CHARACTERIZATION OF THE MOUSE CYTOSOLIC Phosphoenolpyruvate Carboxykinase (GTP) GENE : EVIDENCE FOR TISSUE-SPECIFIC HYPERSENSITIVE SITES
Molecular and Cellular Endocrinology, 1999Co-Authors: Christine P. Williams, Mark A Magnuson, Daryl K Granner, Catherine Postic, Danielle Robin, Pierre Robin, Joseph Parrinello, Kathy D. Shelton, Richard L. Printz, Claude ForestAbstract:Abstract A 72 kilobase pair DNA fragment that contains the mouse Phosphoenolpyruvate Carboxykinase (PEPCK) gene locus, pck1, was isolated from a genomic bacterial artificial chromosome library. The region from ∼−5.5 to +6.6 kilobase pairs relative to the pck1 transcription start site was sequenced and exhibits a high degree of homology to the rat and human genes. Additionally, the chromatin structure of the PEPCK gene in mouse liver resembles that seen in rat. Backcross panel analysis of a microsatellite sequence confirms that the gene is located on chromosome 2. Hypersensitive site analysis was performed on nuclei isolated from the adipocyte cell line 3T3-F442A in the preadipose and adipose states. Several hypersensitive sites are present in the undifferentiated 3T3-F442A cells, before PEPCK mRNA is detected. The same sites are present after differentiation, however, the sensitivity of mHS 3 increases relative to the others. We conclude that the chromatin is open in 3T3-F442A cells and that factors are able to bind in the undifferentiated state but that something else is required for transcription.
-
glucocorticoid receptor camp response element binding protein interaction and the response of the Phosphoenolpyruvate Carboxykinase gene to glucocorticoids
Journal of Biological Chemistry, 1993Co-Authors: E Imai, Keith R Yamamoto, Jeffrey N Miner, J A Mitchell, Daryl K GrannerAbstract:Abstract The Phosphoenolpyruvate Carboxykinase (PEPCK) gene encodes the rate-limiting enzyme in gluconeogenesis. Glucocorticoids enhance PEPCK gene expression through a multicomponent regulatory complex. We show that a full response to glucocorticoids requires two DNA segments: 1) a glucocorticoid response unit (GRU), centered at about position -400, which contains two accessory factor elements (AF1 and AF2) and two glucocorticoid receptor binding sites (GR1 and GR2), and 2) a basal promoter/cyclic AMP response element (E/CRE) at about position -90, which binds the transcription factor CREB. A protein-protein interaction was observed in vitro between GR and CREB that might account for the role of the E/CRE in the glucocorticoid response of the PEPCK gene.