Target "Fructose-1,6-Bisphosphatase 2 (FBP2)" close. ABSTRACT Fructose 2,6-bisphosphate, a known powerful ... &Hers, H.-G. (1980) Biochem.J. (2) An increased supply of plasma fatty acids to the liver caused by the hydrolysis of triglycerides in dietary milk. Inhibition of pyruvate dehydrogenase by acetyl-CoA also increases shunting of pyruvate toward oxaloacetate. Fructose-1,6-bisphosphate triosephosphate-lyase. The enzyme depletes arginine and cells that depend on an external supply die because of arginine starvation.132 In certain leukemic cells, the same situation occurs due to their inability to produce asparagine. Clinical trials in other hematologic malignancies are ongoing (www.clinicaltrials.gov).133, In some cancers, the TCA cycle does not work properly due to mutations in the metabolic enzymes fumarate hydratase (FH), succinate dehydrogenase (SDH), and IDH 1/2. Transcription Start Sites. The liver isoform of pyruvate kinase has several regulatory properties designed to inhibit it so that gluconeogenesis can proceed: (i) strong allosteric inhibition by ATP; (ii) inhibition by alanine, an important gluconeogenic substrate; (iii) dependence on a high level of the activator fructose 1,6-bisphosphate (in order to have the same low Km for phosphoenolpyruvate that the muscle isoform has with or without fructose 1,6-bisphosphate); and (iv) inhibition by phosphorylation by PKA in response to glucagon. As a result, TIGAR promotes generation of NADPH and ribose-5-phosphate (Bensaad et al., 2006). Here, we show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of sarcoma subtypes, revealing an apparent common metabolic feature shared by diverse STSs. K. Matsuura, ... M. Kurokawa, in International Review of Cell and Molecular Biology, 2016. Another targetable glycolytic enzyme is 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). Molecular Weight 428.04 . Fructose 1,6-bisphosphatase is also inhibited by AMP, in contrast to the AMP activation of phosphofructokinase. Glutaminase (GLS) is an enzyme involved in glutaminolysis that is upregulated in several cancers, for example, by overexpression of Myc. The HK2–mitochondria interaction facilitates immortalization of tumor cells. The increased liver uptake of amino acids (derived from protein catabolism in muscle) during fasting provides the carbon skeletons for gluconeogenesis (e.g., alanine is transaminated into pyruvate). John W. Pelley, in Elsevier's Integrated Review Biochemistry (Second Edition), 2012. To overcome this inhibition, four tissue-specific isoforms of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB) exist that are capable of generating fructose-2,6-bisphosphate (F-2,6-P2), the most potent allosteric activator of PFK [94,95]. When the concentration of Fructose-2,6-bisphosphate drops, glycolysis is no longer activated (becomes inhibited) and gluconeogenesis becomes activated (no longer inhibited). This elevation of PFKFB3 results in abnormally high cellular concentrations of F-2,6-P2, causing PFK to be perennially activated. Reviewed-Annotation score: -Experimental evidence at protein level i. Copyright © 2021 Elsevier B.V. or its licensors or contributors. This results in an increase in conversion of F1,6-BP to F6P. La PFK-2/FBPase-2 est un homodimère de deux sous-unités de 55 kDa chacune arrangées en tête-à-tête pour former d'un côté un domaine phosphatase et de l'autre un domaine kinase, ce dernier du côté N-terminal des deux chaînes polypeptidiques. Authors: Ishita Bakshi 1 , Eurwin Suryana 1 , Lewin Small 1 , Lake-Ee Quek 2 , Amanda E Brandon 1 , 3 , Nigel Turner 4 , and Gregory J Cooney 1 , 3 View More View Less. These events therefore represent a major force in driving glucose metabolism in a gluconeogenic direction. FBP26. Comment(s) Also acts on (3S,4R)-ketose 1-phosphates. Raben, in Encyclopedia of Biological Chemistry (Second Edition), 2013. PFK1 can be inhibited by lactate, citrate, ATP, and acyl-CoA. yggF. Le fructose-2,6-bisphosphate est synthétisé par la phosphofructokinase 2 (PFK2) et déphosphorylé en fructose 6-phosphate par la fructose 2,6-bisphosphatase 2 (FBP2). However, unlike normal cells, cancer cells constitutively express high levels of a rarely expressed but highly active isoform of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFKFB3), otherwise known as the inducible or cancer isoform [96,97]. Metabolic reprogramming in cancer cells can be found in glucose and amino acid metabolism as well as during oxidative phosphorylation. Minsuh Seo, ... Yong-Hwan Lee, in Cancer Drug Design and Discovery (Second Edition), 2014. PKM2 but not PKM1 is also activated by serine so that depletion of serine slows down glycolysis to cause a buildup of the glycolytic intermediate used to synthesize serine. The key discovery by Hers and Uyeda was that PFK-2/FBPase-2, or at least one of its isozymes, was indeed the enzyme responsible for the generation as well as the degradation of F2,6BP. FH and SDH are tumor suppressors and mutation leads to loss of function. Il s'agit d'un dimère de deux sous-unités identiques de 55 kDa chacune. By continuing you agree to the use of cookies. Daniel M. Raben, Michael J. Wolfgang, in Reference Module in Biomedical Sciences, 2019. In addition to changes in gene expression, cancer cells use allosteric regulation of glycolytic enzymes by metabolic intermediates to fine-tune the flux of glycolytic intermediates to lactate or the anabolic PPP and serine/glycine synthesis pathway to meet cellular demands. PK catalyzes the final step of glycolysis from phosphoenolpyruvate to pyruvate, which is then either shuttled into the TCA cycle for ATP production or excreted as lactate (see Warburg effect). Theodore S. Widlanski, William Taylor, in Comprehensive Natural Products Chemistry, 1999, A number of phosphorylated molecules such as inositol phosphates and phosphatidic acid play important roles in signal transduction. PPP, pentose phosphate pathway; Fru-1,6-BP, fructose-1,6-bisphosphate; Fru-2,6-BP, fructose-2,6-bisphosphate; GSH, reduced glutathione; ROS, reactive oxygen species; PEP, phosphoenolpyruvate; PKM2, pyruvate kinase M2; NADPH, nicotinamide adenine dinucleotide phosphate; AMP, adenosine monophosphate; ADP, adenosine diphosphate; ATP, adenosine triphosphate; SAICAR, succinylaminoimidazolecarboxamide ribose-5′-phosphate. Le fructose-2,6-bisphosphate, activateur de la phosphofruc tokinase 1 et inhibiteur de la fructose-1,6-bisphosphatase, joue un rôle pivot dans la régulation de l'équilibre entre la … Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) Status. An X-ray structure of the phosphoenzyme intermediate obtained in the fructose-2,6-bisphosphatase catalyzed reaction has been obtained by flash freezing techniques.92 The use of a histidine nucleophile may turn out to be a fairly common motif for specific small-molecule phosphatases. ScienceDirect ® is a registered trademark of Elsevier B.V. ScienceDirect ® is a registered trademark of Elsevier B.V. URL: https://www.sciencedirect.com/science/article/pii/B9780128012383113406, URL: https://www.sciencedirect.com/science/article/pii/B9780123786302000517, URL: https://www.sciencedirect.com/science/article/pii/B9780323074469000131, URL: https://www.sciencedirect.com/science/article/pii/S1937644816300570, URL: https://www.sciencedirect.com/science/article/pii/B9780128012383038162, URL: https://www.sciencedirect.com/science/article/pii/B9780080912837001120, URL: https://www.sciencedirect.com/science/article/pii/B9780123965219000140, URL: https://www.sciencedirect.com/science/article/pii/B978012409547212390X, URL: https://www.sciencedirect.com/science/article/pii/B0124437109005755, URL: https://www.sciencedirect.com/science/article/pii/B9780123864567019122, Phosphofructokinase-2/Fructose Bisphosphatase-2☆, Phosphofructokinase-2/Fructose Bisphosphatase-2, Encyclopedia of Biological Chemistry (Second Edition), Integration of Carbohydrate, Fat, and Amino Acid Metabolism, Elsevier's Integrated Review Biochemistry (Second Edition), Metabolic Regulation of Apoptosis in Cancer, International Review of Cell and Molecular Biology, Bensaad et al., 2006; Cheung et al., 2013; Wanka et al., 2012b, Glucose Metabolism and Hormonal Regulation☆, Encyclopedia of Endocrine Diseases (Second Edition), Enzymes, Enzyme Mechanisms, Proteins, and Aspects of NO Chemistry, Theodore S. Widlanski, William Taylor, in, Targeting Altered Metabolism—Emerging Cancer Therapeutic Strategies, Cancer Drug Design and Discovery (Second Edition), Cancer, Immunology and Inflammation, and Infectious Disease, Pyruvate Carboxylation, Transamination, and Gluconeogenesis, Deregulation of the Cellular Energetics of Cancer Cells. Several targets that are particularly important for metabolic homeostasis of cancer cells can be targeted for therapy (highlighted in blue). Commandez ABIN976706. La phosphorylation du résidu de sérine-32 favorise l'activité phosphatase, tandis que l'absence de phosphorylation de ce résidu favorise l'activité kinase[2]. PFKFB3 is overexpressed in RA patients and PFK15 has shown promising results to attenuate the expression of key proinflammatory cytokines associated with a potential joint destruction (Zou et al., 2017). Origine: Humain. As a p53-inducible gene, it is presumably a tumor suppressor. La phosphofructokinase-2 (PFK-2) ou fructose-bisphosphatase-2 (FBPase-2) est une enzyme bifonctionnelle, dotée à la fois d'une activité kinase et d'une activité phosphatase, qui catalyse les réactions : Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Organism. Some ketogenesis occurs in the liver, especially with prolonged fasting, with ketone bodies primarily going to muscle as an alternative fuel. La dernière modification de cette page a été faite le 20 février 2017 à 03:23. HK2 inhibition has shown some efficacy in patients with solid tumors at high concentration. They are often stimulated by the accumulation of upstream metabolites and inhibited by the accumulation of downstream metabolites. Glucocorticoids, acting via the glucocorticoid receptor, bind to the responsive element on promoters of PEPCK and glucose-6-phosphatase, and up-regulate transcription of both genes. Also, Fructose-2,6-bisphosphate is an allosteric inhibitor of Fructose-1,6-bisphosphatase and, thus, inhibits gluconeogenesis. Indeed, via the production of the antioxidant NADPH, TIGAR reduces the cellular level of ROS that can cause genome instability (Bensaad et al., 2006). Function i. Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate. This leads to an increase in its F2,6BPase activity and a concomitant loss of its PFK-2 activity. Due to the role of PFK1 in fine-tuning cancer metabolism, altering its regulation offers an intriguing drug target. ROS inhibits PKM2, thus ensuring increased PPP flux, but not PKM1, by oxidizing a cysteine that is unique to PKM2. Ces sous-unités possèdent chacune un domaine kinase et un domaine phosphatase. Fructose-2,6-bisphosphatase. Fructose 1,6-bisphosphatase is also a key player in treating type 2 diabetes. 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