Fructose 2,6-bisphosphate

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Fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate.svg
Names
IUPAC name
2,6-Di-O-phosphono-β-D-fructofuranose
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
MeSH fructose+2,6-bisphosphate
PubChem CID
  • InChI=1S/C6H14O12P2/c7-2-6(18-20(13,14)15)5(9)4(8)3(17-6)1-16-19(10,11)12/h3-5,7-9H,1-2H2,(H2,10,11,12)(H2,13,14,15)/t3-,4-,5+,6+/m1/s1 Yes check.svgY
    Key: YXWOAJXNVLXPMU-ZXXMMSQZSA-N Yes check.svgY
  • C([C@@H]1[C@H]([C@@H]([C@](O1)(CO)OP(=O)(O)O)O)O)OP(=O)(O)O
Properties
C6H14O12P2
Molar mass 340.114 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Fructose 2,6-bisphosphate, abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 (PFK-1) and fructose 1,6-bisphosphatase (FBPase-1) to regulate glycolysis and gluconeogenesis. [1] Fru-2,6-P2 itself is synthesized and broken down in either direction by the integrated bifunctional enzyme phosphofructokinase 2 (PFK-2/FBPase-2), which also contains a phosphatase domain and is also known as fructose-2,6-bisphosphatase. [2] Whether the kinase and phosphatase domains of PFK-2/FBPase-2 are active or inactive depends on the phosphorylation state of the enzyme.

Contents

Fructose-6-p-phosphate is phosphorylated by the kinase domain of PFK-2/FBPase-2 to Fru-2,6-P2 when PFK-2/FBPase-2 is active in a dephosphorylated state. This dephosphorylated state is favored by high levels of insulin, which activates the phosphatase domain.

The synthesis of Fru-2,6-P2 is performed through a bifunctional enzyme containing both PFK-2 and FBPase-2, which is dephosphorylated, allowing the PFK-2 portion to phosphorylate fructose 6-phosphate using ATP. The breakdown of Fru-2,6-P2 is catalyzed by the phosphorylation of the bifunctional enzyme, which allows FBPase-2 to dephosphorylate fructose 2,6-bisphosphate to produce fructose 6-phosphate and Pi. [3]

Effects on glucose metabolism

Fru-2,6-P2 strongly activates glucose breakdown in glycolysis through allosteric modulation (activation) of phosphofructokinase 1 (PFK-1). Elevated expression of Fru-2,6-P2 levels in the liver allosterically activates phosphofructokinase 1 by increasing the enzyme’s affinity for fructose 6-phosphate, while decreasing its affinity for inhibitory ATP and citrate. At physiological concentration, PFK-1 is almost completely inactive, but interaction with Fru-2,6-P2 activates the enzyme to stimulate glycolysis and enhance breakdown of glucose. [4]

Cellular stress as a result of oncogenesis or DNA damage among others, activates certain genes by the tumor suppressor p53. One such gene encodes TP53-inducible glycolysis and apoptosis regulator (TIGAR); an enzyme that inhibits glycolysis, monitors the cellular levels of reactive oxygen species, and protects cells from apoptosis. The structure of TIGAR is shown to be nearly identical to FBPase-2 on the bifunctional enzyme. TIGAR removes the allosteric effector, Fru-2,6-P2., therefore the activator does not enhance the affinity of the enzyme (PFK1) for its substrate (fructose 6-phosphate). Furthermore, TIGAR also removes the glycolytic intermediate fructose 1,6-bisphosphate, the product of the PFK catalyzed third reaction of glycolysis and the substrate for the following aldolase fourth reaction of glycolysis. [5]

Production regulation

The concentration of Fru-2,6-P2 in cells is controlled through regulation of the synthesis and breakdown by PFK-2/FBPase-2. The primary regulators of this are the hormones insulin, glucagon, and epinephrine which affect the enzyme through phosphorylation/dephosphorylation reactions.

Activation of the glucagon receptor (primarily coupled to Gs) triggers production of cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA, or cAMP-dependent protein kinase). PKA phosphorylates the PFK-2/FBPase-2 enzyme at an NH2-terminal Ser residue with ATP to activate the FBPase-2 activity and inhibit the PFK-2 activity of the enzyme, thus reducing levels of Fru-2,6-P2 in the cell. With decreasing amounts of Fru-2,6-P2, glycolysis becomes inhibited while gluconeogenesis is activated.

Insulin triggers the opposite response by activating protein phosphatases that dephosphorylate PFK-2, thereby inhibiting the FBPase-2 domain. With additional Fru-2,6-P2 present, activation of PFK-1 occurs to stimulate glycolysis while inhibiting gluconeogenesis. [3] [6] As of 2023, which specific phosphatases are involved in mediating insulin's downstream effect specifically on PFK-2 are currently unclear; protein phosphatase 1 is known to be involved in mediating insulin's downstream effect of dephosphorylating glycogen synthase, thereby activating it.

Regulation of sucrose production

Fru-2,6-P2 plays an important role in the regulation of triose phosphates, the end products of the Calvin Cycle. In the Calvin Cycle, 5/6th of triose phosphates are recycled to make ribulose 1,5-bisphosphate. The remaining 1/6 of triose phosphate can be converted into sucrose or stored as starch. Fru-2,6-P2 inhibits production of fructose 6-phosphate, a necessary element for sucrose synthesis. When the rate of photosynthesis in the light reactions is high, triose phosphates are constantly produced and the production of Fru-2,6-P2 is inhibited, thus producing sucrose. Fru-2,6-P2 production is activated when plants are in the dark and photosynthesis and triose phosphates are not produced. [7]

See also

Related Research Articles

<span class="mw-page-title-main">Glycolysis</span> Series of interconnected biochemical reactions

Glycolysis is the metabolic pathway that converts glucose into pyruvate and, in most organisms, occurs in the liquid part of cells. The free energy released in this process is used to form the high-energy molecules adenosine triphosphate (ATP) and reduced nicotinamide adenine dinucleotide (NADH). Glycolysis is a sequence of ten reactions catalyzed by enzymes.

<span class="mw-page-title-main">Kinase</span> Enzyme catalyzing transfer of phosphate groups onto specific substrates

In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In vertebrates, gluconeogenesis occurs mainly in the liver and, to a lesser extent, in the cortex of the kidneys. It is one of two primary mechanisms – the other being degradation of glycogen (glycogenolysis) – used by humans and many other animals to maintain blood sugar levels, avoiding low levels (hypoglycemia). In ruminants, because dietary carbohydrates tend to be metabolized by rumen organisms, gluconeogenesis occurs regardless of fasting, low-carbohydrate diets, exercise, etc. In many other animals, the process occurs during periods of fasting, starvation, low-carbohydrate diets, or intense exercise.

<span class="mw-page-title-main">Glucagon</span> Peptide hormone

Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises the concentration of glucose and fatty acids in the bloodstream and is considered to be the main catabolic hormone of the body. It is also used as a medication to treat a number of health conditions. Its effect is opposite to that of insulin, which lowers extracellular glucose. It is produced from proglucagon, encoded by the GCG gene.

<span class="mw-page-title-main">Fructose 1,6-bisphosphatase</span> Class of enzymes

The enzyme fructose bisphosphatase (EC 3.1.3.11; systematic name D-fructose-1,6-bisphosphate 1-phosphohydrolase) catalyses the conversion of fructose-1,6-bisphosphate to fructose 6-phosphate in gluconeogenesis and the Calvin cycle, which are both anabolic pathways:

<span class="mw-page-title-main">Phosphofructokinase 1</span> Class of enzymes

Phosphofructokinase-1 (PFK-1) is one of the most important regulatory enzymes of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors. PFK-1 catalyzes the important "committed" step of glycolysis, the conversion of fructose 6-phosphate and ATP to fructose 1,6-bisphosphate and ADP. Glycolysis is the foundation for respiration, both anaerobic and aerobic. Because phosphofructokinase (PFK) catalyzes the ATP-dependent phosphorylation to convert fructose-6-phosphate into fructose 1,6-bisphosphate and ADP, it is one of the key regulatory steps of glycolysis. PFK is able to regulate glycolysis through allosteric inhibition, and in this way, the cell can increase or decrease the rate of glycolysis in response to the cell's energy requirements. For example, a high ratio of ATP to ADP will inhibit PFK and glycolysis. The key difference between the regulation of PFK in eukaryotes and prokaryotes is that in eukaryotes PFK is activated by fructose 2,6-bisphosphate. The purpose of fructose 2,6-bisphosphate is to supersede ATP inhibition, thus allowing eukaryotes to have greater sensitivity to regulation by hormones like glucagon and insulin.

<span class="mw-page-title-main">PFP (enzyme)</span> Class of enzymes

Diphosphate—fructose-6-phosphate 1-phosphotransferase also known as PFP is an enzyme of carbohydrate metabolism in plants and some bacteria. The enzyme catalyses the reversible interconversion of fructose 6-phosphate and fructose 1,6-bisphosphate using inorganic pyrophosphate as the phosphoryl donor:

<span class="mw-page-title-main">Pyruvate kinase</span> Class of enzymes

Pyruvate kinase is the enzyme involved in the last step of glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate (PEP) to adenosine diphosphate (ADP), yielding one molecule of pyruvate and one molecule of ATP. Pyruvate kinase was inappropriately named before it was recognized that it did not directly catalyze phosphorylation of pyruvate, which does not occur under physiological conditions. Pyruvate kinase is present in four distinct, tissue-specific isozymes in animals, each consisting of particular kinetic properties necessary to accommodate the variations in metabolic requirements of diverse tissues.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<span class="mw-page-title-main">Phosphofructokinase 2</span> Class of enzymes

Phosphofructokinase-2 (6-phosphofructo-2-kinase, PFK-2) or fructose bisphosphatase-2 (FBPase-2), is an enzyme indirectly responsible for regulating the rates of glycolysis and gluconeogenesis in cells. It catalyzes formation and degradation of a significant allosteric regulator, fructose-2,6-bisphosphate (Fru-2,6-P2) from substrate fructose-6-phosphate. Fru-2,6-P2 contributes to the rate-determining step of glycolysis as it activates enzyme phosphofructokinase 1 in the glycolysis pathway, and inhibits fructose-1,6-bisphosphatase 1 in gluconeogenesis. Since Fru-2,6-P2 differentially regulates glycolysis and gluconeogenesis, it can act as a key signal to switch between the opposing pathways. Because PFK-2 produces Fru-2,6-P2 in response to hormonal signaling, metabolism can be more sensitively and efficiently controlled to align with the organism's glycolytic needs. This enzyme participates in fructose and mannose metabolism. The enzyme is important in the regulation of hepatic carbohydrate metabolism and is found in greatest quantities in the liver, kidney and heart. In mammals, several genes often encode different isoforms, each of which differs in its tissue distribution and enzymatic activity. The family described here bears a resemblance to the ATP-driven phospho-fructokinases; however, they share little sequence similarity, although a few residues seem key to their interaction with fructose 6-phosphate.

<span class="mw-page-title-main">Fructose 1,6-bisphosphate</span> Chemical compound

Fructose 1,6-bisphosphate, known in older publications as Harden-Young ester, is fructose sugar phosphorylated on carbons 1 and 6. The β-D-form of this compound is common in cells. Upon entering the cell, most glucose and fructose is converted to fructose 1,6-bisphosphate.

<span class="mw-page-title-main">Phosphofructokinase</span> Enzyme in glycolysis

Phosphofructokinase (PFK) is a kinase enzyme that phosphorylates fructose 6-phosphate in glycolysis.

<span class="mw-page-title-main">Fructose-bisphosphate aldolase</span>

Fructose-bisphosphate aldolase, often just aldolase, is an enzyme catalyzing a reversible reaction that splits the aldol, fructose 1,6-bisphosphate, into the triose phosphates dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P). Aldolase can also produce DHAP from other (3S,4R)-ketose 1-phosphates such as fructose 1-phosphate and sedoheptulose 1,7-bisphosphate. Gluconeogenesis and the Calvin cycle, which are anabolic pathways, use the reverse reaction. Glycolysis, a catabolic pathway, uses the forward reaction. Aldolase is divided into two classes by mechanism.

Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase and is involved in mammalian starch and sucrose metabolism. It catalyzes the transfer of a phosphate group from 1,3-bisphosphoglycerate to glucose-1-phosphate, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate.

<span class="mw-page-title-main">Enzyme activator</span> Molecules which increase enzyme activity

Enzyme activators are molecules that bind to enzymes and increase their activity. They are the opposite of enzyme inhibitors. These molecules are often involved in the allosteric regulation of enzymes in the control of metabolism. An example of an enzyme activator working in this way is fructose 2,6-bisphosphate, which activates phosphofructokinase 1 and increases the rate of glycolysis in response to the hormone glucagon. In some cases, when a substrate binds to one catalytic subunit of an enzyme, this can trigger an increase in the substrate affinity as well as catalytic activity in the enzyme's other subunits, and thus the substrate acts as an activator.

<span class="mw-page-title-main">PFKFB3</span> Protein-coding gene in the species Homo sapiens

PFKFB3 is a gene that encodes the 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 enzyme in humans. It is one of 4 tissue-specific PFKFB isoenzymes identified currently (PFKFB1-4).

<span class="mw-page-title-main">PFKFB2</span> Protein-coding gene in the species Homo sapiens

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 2 is an enzyme that in humans is encoded by the PFKFB2 gene.

Bisphosphate may refer to:

<span class="mw-page-title-main">TP53-inducible glycolysis and apoptosis regulator</span> Protein-coding gene in the species Homo sapiens

The TP53-inducible glycolysis and apoptosis regulator (TIGAR) also known as fructose-2,6-bisphosphatase TIGAR is an enzyme that in humans is encoded by the C12orf5 gene.

<span class="mw-page-title-main">Glucagon (medication)</span> Medication that increases blood sugar levels

Glucagon, sold under the brand name Baqsimi among others, is a medication and hormone. As a medication it is used to treat low blood sugar, beta blocker overdose, calcium channel blocker overdose, and those with anaphylaxis who do not improve with epinephrine. It is given by injection into a vein, muscle, or under the skin. A version given in the nose is also available.

References

  1. ↑ Alfarouk, Khalid O.; Verduzco, Daniel; Rauch, Cyril; Muddathir, Abdel Khalig; Bashir, Adil H. H.; Elhassan, Gamal O.; Ibrahim, Muntaser E.; Orozco, Julian David Polo; Cardone, Rosa Angela; Reshkin, Stephan J.; Harguindey, Salvador (18 December 2014). "Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question". Oncoscience. 1 (12): 777–802. doi: 10.18632/oncoscience.109 . PMC   4303887 . PMID   25621294.
  2. ↑ Wu C, Khan SA, Peng LJ, Lange AJ (2006). "Roles for fructose-2,6-bisphosphate in the control of fuel metabolism: beyond its allosteric effects on glycolytic and gluconeogenic enzymes". Adv. Enzyme Regul. 46 (1): 72–88. doi:10.1016/j.advenzreg.2006.01.010. PMID   16860376.
  3. 1 2 Kurland IJ, Pilkis SJ (June 1995). "Covalent control of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase: insights into autoregulation of a bifunctional enzyme". Protein Sci. 4 (6): 1023–37. doi:10.1002/pro.5560040601. PMC   2143155 . PMID   7549867.
  4. ↑ Lange AJ. "fructose-2,6-bisphosphate". University of Minnesota. Archived from the original on 2010-06-12.
  5. ↑ Garret, Reginald H.; Grisham, Charles M. (2013). Biochemistry. Belmont, CA: Brooks/Cole Cengage Learning. p. 730. ISBN   978-1-133-10629-6.
  6. ↑ Smith WE, Langer S, Wu C, Baltrusch S, Okar DA (June 2007). "Molecular coordination of hepatic glucose metabolism by the 6-phosphofructo-2-kinase/fructose-2,6- bisphosphatase:glucokinase complex". Mol. Endocrinol. 21 (6): 1478–87. doi:10.1210/me.2006-0356. PMID   17374851.
  7. ↑ Nielsen TH, Rung JH, Villadsen D (November 2004). "Fructose-2,6-bisphosphate: a traffic signal in plant metabolism". Trends Plant Sci. 9 (11): 556–63. doi:10.1016/j.tplants.2004.09.004. PMID   15501181.
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