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Review article

6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis

Mark H. RIDER, Luc BERTRAND, Didier VERTOMMEN, Paul A. MICHELS, Guy G. ROUSSEAU, Louis HUE
Biochemical Journal Aug 01, 2004, 381 (3) 561-579; DOI: 10.1042/BJ20040752
Mark H. RIDER
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 75, Avenue Hippocrate, B-1200 Brussels, Belgium
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  • For correspondence: rider@horm.ucl.ac.be
Luc BERTRAND
Division of Cardiology, Université Catholique de Louvain, 55, Avenue Hippocrate, B-1200 Brussels, Belgium
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Didier VERTOMMEN
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 75, Avenue Hippocrate, B-1200 Brussels, Belgium
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Paul A. MICHELS
Research Unit for Tropical Diseases, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 75, Avenue Hippocrate, B-1200 Brussels, Belgium
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Guy G. ROUSSEAU
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 75, Avenue Hippocrate, B-1200 Brussels, Belgium
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Louis HUE
Hormone and Metabolic Research Unit, Université Catholique de Louvain and Christian de Duve Institute of Cellular Pathology, 75, Avenue Hippocrate, B-1200 Brussels, Belgium
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Abstract

Fru-2,6-P2 (fructose 2,6-bisphosphate) is a signal molecule that controls glycolysis. Since its discovery more than 20 years ago, inroads have been made towards the understanding of the structure–function relationships in PFK-2 (6-phosphofructo-2-kinase)/FBPase-2 (fructose-2,6-bisphosphatase), the homodimeric bifunctional enzyme that catalyses the synthesis and degradation of Fru-2,6-P2. The FBPase-2 domain of the enzyme subunit bears sequence, mechanistic and structural similarity to the histidine phosphatase family of enzymes. The PFK-2 domain was originally thought to resemble bacterial PFK-1 (6-phosphofructo-1-kinase), but this proved not to be correct. Molecular modelling of the PFK-2 domain revealed that, instead, it has the same fold as adenylate kinase. This was confirmed by X-ray crystallography. A PFK-2/FBPase-2 sequence in the genome of one prokaryote, the proteobacterium Desulfovibrio desulfuricans, could be the result of horizontal gene transfer from a eukaryote distantly related to all other organisms, possibly a protist. This, together with the presence of PFK-2/FBPase-2 genes in trypanosomatids (albeit with possibly only one of the domains active), indicates that fusion of genes initially coding for separate PFK-2 and FBPase-2 domains might have occurred early in evolution. In the enzyme homodimer, the PFK-2 domains come together in a head-to-head like fashion, whereas the FBPase-2 domains can function as monomers. There are four PFK-2/FBPase-2 isoenzymes in mammals, each coded by a different gene that expresses several isoforms of each isoenzyme. In these genes, regulatory sequences have been identified which account for their long-term control by hormones and tissue-specific transcription factors. One of these, HNF-6 (hepatocyte nuclear factor-6), was discovered in this way. As to short-term control, the liver isoenzyme is phosphorylated at the N-terminus, adjacent to the PFK-2 domain, by PKA (cAMP-dependent protein kinase), leading to PFK-2 inactivation and FBPase-2 activation. In contrast, the heart isoenzyme is phosphorylated at the C-terminus by several protein kinases in different signalling pathways, resulting in PFK-2 activation.

  • catalysis
  • evolution
  • fructose 2,6-bisphosphate
  • gene
  • glycolysis
  • phosphorylation

Abbreviations: ACC, acetyl-CoA carboxylase; AK, adenylate kinase; AMPK, AMP-activated protein kinase; Ca/CAMK, Ca2+/calmodulin-activated protein kinase; C/EBP, CCAAT/enhancer-binding protein; EGF, epidermal growth factor; FBPase-1, fructose-1,6-bisphosphatase; FBPase-2, fructose-2,6-bisphosphatase; Fru-6-P, fructose 6-phosphate; Fru-2,6-P2, fructose 2,6-bisphosphate; GAP, GTPase-activating protein; GLUT4, glucose transporter 4; GR, glucocorticoid receptor; GRU, glucocorticoid-response unit; HNF, hepatocyte nuclear factor; MAPK, mitogen-activated protein kinase; NF-1, nuclear factor 1; OC, Onecut; PDK, phosphoinositide-dependent protein kinase; PEPCK, phosphoenolpyruvate carboxykinase; PFK-1, 6-phosphofructo-1-kinase; PFK-2, 6-phosphofructo-2-kinase; iPFK-2, inducible PFK-2; PI3K, phosphoinositide 3-kinase; PKA, cAMP-dependent protein kinase; PKB, protein kinase B; PKC, protein kinase C; p70S6k, p70 ribosomal protein S6 kinase; 3D, three-dimensional; WISK, wortmannin-sensitive, insulin-stimulated protein kinase

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August 2004

Volume: 381 Issue: 3

Biochemical Journal: 381 (3)
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6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis
Mark H. RIDER, Luc BERTRAND, Didier VERTOMMEN, Paul A. MICHELS, Guy G. ROUSSEAU, Louis HUE
Biochemical Journal Aug 2004, 381 (3) 561-579; DOI: 10.1042/BJ20040752
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6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis
Mark H. RIDER, Luc BERTRAND, Didier VERTOMMEN, Paul A. MICHELS, Guy G. ROUSSEAU, Louis HUE
Biochemical Journal Aug 2004, 381 (3) 561-579; DOI: 10.1042/BJ20040752

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  • Article
    • Abstract
    • INTRODUCTION
    • THE PFK-2/FBPase-2 GENES IN MAMMALS
    • THE PFK-2 REACTION: CATALYSIS, SITE-DIRECTED MUTAGENESIS AND MODELLING
    • STRUCTURE OF PFK-2/FBPase-2
    • EVOLUTION OF PFK-2/FBPase-2
    • TRANSCRIPTIONAL CONTROL OF MAMMALIAN PFK-2/FBPase-2
    • MECHANISMS OF CONTROL OF PFK-2 AND FBPase-2 BY PROTEIN PHOSPHORYLATION
    • PHOSPHORYLATION OF PFK-2/FBPase-2 ISOENZYMES AND THE CONTROL OF GLYCOLYSIS
    • CONCLUDING REMARKS
    • Acknowledgments
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Keywords

catalysis
evolution
fructose 2,6-bisphosphate
gene
glycolysis
phosphorylation

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