6-phosphofructo-2-kinase

Pilkis SJ et al 6-Phosphofructo-2-kinase/fructose-2,6-bisphospha-tase A metabolic signaling enzyme. Annu Rev Biochem 1995 64 799. 

How does phosphorylation affect the activity of phosphofructo-2-kinase (PFK-2), the enzyme that synthesizes fructose 2,6-bisphosphate, a regulator of glycolysis There are two possible answers it either activates it or inactivates it. The simplest approach to the question is just to flip a coin. You should stand a 50 50 chance of getting it right. The next simplest way is to figure it out. 

To distinguish between the two enzymes, the glycolytic enzyme is identified as phosphofructo-1-kinase, abbreviated to PFK-1. The regulatory enzyme, phosphofructo-2-kinase, is abbreviated to PFK-2. 

This enzyme [EC 2.7.1.11], also known as phosphohexo-kinase and phosphofructokinase 1, catalyzes the reaction of ATP with D-fructose 6-phosphate to produce ADP and D-fructose 1,6-bisphosphate. Both D-tagatose 6-phosphate and sedoheptulose 7-phosphate can act as the sugar substrate. UTP, CTP, GTP, and ITP all can act as the nucleotide substrate. This enzyme is distinct from that of 6-phosphofructo-2-kinase. See also ATP GTP Depletion... 

SORBITOL DEHYDROGENASE FRUCTOSE-1,6-BISPHOSPHATASE FRUCTOSE-2,6-BISPHOSPHATASE D-Fructose 2,6-bisphosphate, 6-PHOSPHOFRUCTO-2-KINASE Fructose-1,6-bisphosphate aldolase, ALDOLASE... 

PYRUVATE, WATER DIKINASE PHOSPHOFRUCTOKINASE ATP GTP DEPLETION 6-PHOSPHOFRUCTO-2-KINASE 6-Phospho-D-galactose,... 

The membrane-associated Akt kinase is now a substrate for protein kinase PDKl that phosphorylates a specific Thr and Ser residue of Akt kinase. The double phosphorylation converts Akt kinase to the active form. It is assumed that the Akt kinase now dissociates from the membrane and phosphorylates cytosolic substrates such as glycogen synthase kinase, 6-phosphofructo-2-kinase and ribosomal protein S6 kinase, p70 . According to this mechanism, Akt kinase regulates central metabolic pathways of the cell. Furthermore, it has a promoting influence on cell division and an inhibitory influence on programmed cell death, apoptosis. A role in apoptosis is suggested by the observation that a component of the apoptotic program. Bad protein (see Chapter 15) has been identified as a substrate of Akt kinase. 

Phosphorylated IRS-1 activates a second signaling pathway by interacting with an 85-kDa SH2-containing protein that is a subunit of phophatidylinositol 3-kinase.384 386 This activates the 110-kDa catalytic subunit of the 3-kinase, which catalyzes formation of phosphatidylinositol 3-phosphate as well as Ptdlns (3,4)P2 and Ptdlns (3,4,5)P3.387/387a These compounds, which remain within membranes, activate other branches of the signaling cascade, some of which may converge with those of the MAP kinase cascade. However, there appears to be specific activation of a ribosomal Ser/Thr kinase that, among other activities, phosphorylates ribosomal protein S6, a component of the small ribosomal subunit.388 It also phosphorylates some isoforms of protein kinase C and other enzymes. Ptdlns 3-kinase may also activate 6-phosphofructo-2-kinase (Fig. 11-2, step ti).384/388... 

Phosphofructo-2-kinase Enzymes of glycogen synthesis Dephosphorylation... 

The effects of ATP, AMP, and fructose 2,6-bisphos-phate on phosphofructokinase have been discussed in Chapter 11, Section C. Fructose 2,6-P2 is a potent allosteric activator of phosphofructokinase and a strong competitive inhibitor of fructose 1,6-bisphosphatase (Fig. 11-2). It is formed from fructose 6-P and ATP by the 90-kDa bifunctional phosphofructo-2-kinase/ fructose 2,6-bisphosphatase. Thus, the same protein forms and destroys this allosteric effector. Since the bifunctional enzyme is present in very small amounts, the rate of ATP destruction from the substrate cycling is small. 

Shin DJ and McGrane MM (1997) Vitamin A regulates genes involved in hepatic gluconeogenesis in mice phosphoenolpyruvate carhoxykinase, fructose-1,6-his-phosphatase and 6-phosphofructo-2-kinase/fructose-2,6-hisphosphatase./ourna/o/ Nutrition 127,1274-8. 

C.A. Hasemann, E.S. Istvan, K. Uyeda, and J. Deisenhofer. 1996. The crystal structure of the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase reveals distinct domain homologies Structure 4 1017-1029. (PubMed)... 

Fukusima, Y, Hayashi, M, Fujiwara, M, Miyagawa, T, Yoshikawa, G, Yano, T, Nakajima, H, Enzymatic synthesis of carbocyclic analogue of fructose 2,6-bisphosphate with 6-phosphofructo-2-kinase, Chem. Lett., 575-576, 1998. 

The crystal structure of the entire 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase, a key bifunctional regulator of both glycolysis and gluconeogenesis, has been solved at 2.0 A resolution. The entire enzyme is a homodimer of 55kDa subunits arranged in a head-to-head fashion, with each monomer consisting of an independent kinase and phosphatase domain. The location of y-5 -ATP and inorganic phosphate in the kinase and phosphatase domains,... 

The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 277(34) 30778-30783. doi 10.1074/jbc. 

Almeida A, Moncada S, Bolanos JP. 2003. Nitric oxide switches on glycolysis through the AMP protein kinase and 6-phosphofructo-2-kinase pathway. Nat Cell Biol 6 ... 

Wilson, J. E. 2003. Isozymes of mammalian hexokinase Structure, function and subcellular location. J. Exp. Biol. 206 2049-2057. Lee. Y. H., Li, Y., Uyeda. K., and Hasemann. C. A. 2003. Lissue-spe-cific structure/funclion differentiation of the five isoforms of 6-phosphofructo-2 kinase/lruclose-2,6 bisphosphatase. 7-... 

Fructose-2,6biP is produced when the glycolytic intermediate fructose-6P is phosphorylated by the enzyme 6-phosphofructo-2-kinase. Fructose-2,6biP can be converted back into fructose-6P by the catalytic action of fructose-2,6 biphosphatase. Interestingly, fructose-2,6 biphosphatase/6-phosphofructo-2-kinase is a single enzyme that carries out both catalytic functions. The two activities of this enzyme are covalently regulated that is, cyclic AMP-dependent protein kinase... 

Activation of Akt kinase proceeds in a multi-step process with regulation by PtdIns(3,4,5)P3 as the critical step. PtdIns(3,4,5)P3 binds to the PH domain of Akt kinase and thereby recruits the enzyme to the cell membrane. This step is thought to be a prerequisite for a subsequent phosphorylation of a Thr residue in the activation loop (see Chapter 7 on protein kinases) and an N-terminal Ser residue of Akt. The protein kinase responsible for this step is named phosphoinositide-dependent protein kinase 1 (PDK1, review Vanhaesebroeck and Alessi, 2000), and this also contains a PH domain with high affinity for PtdIns(3,4,5)P3. Membrane targeting and the double phosphorylation activate Akt, allowing the phosphorylation of downstream substrates like the Bad protein (see Section 15.7.1), pro-caspase 9, the transription factor CREB (see Section 1.4.5.2), glycogen synthase kinase (GSK), and 6-phosphofructo-2-kinase. 

Pilkis, S. J., T. H. Claus, 1. J. Kurland, and A. J. Lange. 1995. 6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase a metabolic signaling enzyme. Arm. Rev. Biochem. 64 799-835. 

Phosphofructo-2-kinase-Fructose-2,6-bisphosphatase (PFK2-FBPase2)... 

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