Fructose bisphosphatase
Encyclopedia
Fructose bisphosphatase is an enzyme
in the liver
that converts fructose-1,6-bisphosphate to fructose 6-phosphate
in gluconeogenesis
(the synthesis of glucose
from smaller substrates). Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase
, which is involved in the process of glycolysis
. These enzymes only catalyse the reaction in one direction each, and are regulated by metabolites such as fructose 2,6-bisphosphate
so that high activity of one of the two enzymes is accompanied by low activity of the other. It is involved in many different metabolic pathways
and found in most organism
s. FBPase requires metal ion
s for catalysis (Mg
2+ and Mn
2+ being preferred) and the enzyme is potently inhibited by Li
+.
The fold
of fructose-1,6-bisphosphatase from pig
was noted to be identical to that of inositol-1-phosphatase (IMPase). Inositol
polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif
(Asp
-Pro
-Ile
/Leu
-Asp-Gly
/Ser
-Thr
/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial
and yeast
IMPase homologues
. It has been suggested that these protein
s define an ancient structurally conserved family involved in diverse metabolic
pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone
metabolism
.
Three different groups of FBPases have been identified in eukaryotes and bacteria
(FBPase I-III). None of these groups have been found in archaea
so far, though a new group of FBPases (FBPase IV) which also show inositol monophosphatase
activity has recently been identified in archaea.
A new group of FBPases (FBPase V) is found in thermophilic archaea and the hyperthermophilic bacterium Aquifex aeolicus
. The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organism
s. A structural
study suggests that FBPase V has a novel fold
for a sugar
phosphatase
, forming a four-layer alpha-beta-beta-alpha sandwich, unlike the more usual five-layered alpha-beta-alpha-beta-alpha arrangement. The arrangement of the catalytic side chain
s and metal ligands was found to be consistent with the three-metal ion
assisted catalysis mechanism proposed for other FBPases.
The fructose 1,6-bisphosphatases found within the Firmicutes
(low GC Gram-positive
bacteria) do not show any significant sequence
similarity to the enzymes from other organism
s. The Bacillus subtilis
enzyme is inhibited by AMP
, though this can be overcome by phosphoenolpyruvate
, and is dependent on Mn(2+). Mutant
s lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as malate
and glycerol
.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
that converts fructose-1,6-bisphosphate to fructose 6-phosphate
Fructose 6-phosphate
Fructose 6-phosphate is fructose sugar phosphorylated on carbon 6 . The β-D-form of this compound is very common in cells. The vast majority of glucose and fructose entering a cell will become converted to this at some point...
in gluconeogenesis
Gluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
(the synthesis of glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
from smaller substrates). Fructose bisphosphatase catalyses the reverse of the reaction which is catalysed by phosphofructokinase
Phosphofructokinase
Phosphofructokinase-1 is the most important regulatory enzyme of glycolysis. It is an allosteric enzyme made of 4 subunits and controlled by many activators and inhibitors...
, which is involved in the process of glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
. These enzymes only catalyse the reaction in one direction each, and are regulated by metabolites such as fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate
Fructose 2,6-bisphosphate abbreviated Fru-2,6-P2, is a metabolite that allosterically affects the activity of the enzymes phosphofructokinase 1 and fructose 1,6-bisphosphatase to regulate glycolysis and gluconeogenesis...
so that high activity of one of the two enzymes is accompanied by low activity of the other. It is involved in many different metabolic pathways
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
and found in most organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
s. FBPase requires metal ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s for catalysis (Mg
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...
2+ and Mn
Manganese
Manganese is a chemical element, designated by the symbol Mn. It has the atomic number 25. It is found as a free element in nature , and in many minerals...
2+ being preferred) and the enzyme is potently inhibited by Li
Lithium
Lithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number 3. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
+.
The fold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
of fructose-1,6-bisphosphatase from pig
Pig
A pig is any of the animals in the genus Sus, within the Suidae family of even-toed ungulates. Pigs include the domestic pig, its ancestor the wild boar, and several other wild relatives...
was noted to be identical to that of inositol-1-phosphatase (IMPase). Inositol
Inositol
Inositol or cyclohexane-1,2,3,4,5,6-hexol is a chemical compound with formula 6126 or 6, a sixfold alcohol of cyclohexane. It exists in nine possible stereoisomers, of which the most prominent form, widely occurring in nature, is cis-1,2,3,5-trans-4,6-cyclohexanehexol, or myo-inositol...
polyphosphate 1-phosphatase (IPPase), IMPase and FBPase share a sequence motif
Sequence motif
In genetics, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and has, or is conjectured to have, a biological significance...
(Asp
Aspartic acid
Aspartic acid is an α-amino acid with the chemical formula HOOCCHCH2COOH. The carboxylate anion, salt, or ester of aspartic acid is known as aspartate. The L-isomer of aspartate is one of the 20 proteinogenic amino acids, i.e., the building blocks of proteins...
-Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-Ile
Isoleucine
Isoleucine is an α-amino acid with the chemical formula HO2CCHCHCH2CH3. It is an essential amino acid, which means that humans cannot synthesize it, so it must be ingested. Its codons are AUU, AUC and AUA....
/Leu
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
-Asp-Gly
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
/Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-Thr
Threonine
Threonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
/Ser) which has been shown to bind metal ions and participate in catalysis. This motif is also found in the distantly-related fungal, bacterial
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
and yeast
Saccharomyces cerevisiae
Saccharomyces cerevisiae is a species of yeast. It is perhaps the most useful yeast, having been instrumental to baking and brewing since ancient times. It is believed that it was originally isolated from the skin of grapes...
IMPase homologues
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...
. It has been suggested that these protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s define an ancient structurally conserved family involved in diverse metabolic
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly quinone
Quinone
A quinone is a class of organic compounds that are formally "derived from aromatic compounds [such as benzene or naphthalene] by conversion of an even number of –CH= groups into –C– groups with any necessary rearrangement of double bonds," resulting in "a fully conjugated cyclic dione structure."...
metabolism
Metabolism
Metabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
.
Three different groups of FBPases have been identified in eukaryotes and bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
(FBPase I-III). None of these groups have been found in archaea
Archaea
The Archaea are a group of single-celled microorganisms. A single individual or species from this domain is called an archaeon...
so far, though a new group of FBPases (FBPase IV) which also show inositol monophosphatase
Inositol monophosphatase
Inositol monophosphatase , commonly referred to as IMPase, is an enzyme found in all cells and is thought to be key in bipolar disorder...
activity has recently been identified in archaea.
A new group of FBPases (FBPase V) is found in thermophilic archaea and the hyperthermophilic bacterium Aquifex aeolicus
Aquifex aeolicus
Aquifex aeolicus is a rod-shaped prokaryote with a length of 2 to 6 micrometers and a diameter of around half a micrometer. It is one of a handful of species in the Aquificae phylum, an unusual group of thermophilic bacteria that are thought to be some of the oldest species of bacteria.A...
. The characterised members of this group show strict substrate specificity for FBP and are suggested to be the true FBPase in these organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
s. A structural
Secondary structure
In biochemistry and structural biology, secondary structure is the general three-dimensional form of local segments of biopolymers such as proteins and nucleic acids...
study suggests that FBPase V has a novel fold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
for a sugar
Sugar
Sugar is a class of edible crystalline carbohydrates, mainly sucrose, lactose, and fructose, characterized by a sweet flavor.Sucrose in its refined form primarily comes from sugar cane and sugar beet...
phosphatase
Phosphatase
A phosphatase is an enzyme that removes a phosphate group from its substrate by hydrolysing phosphoric acid monoesters into a phosphate ion and a molecule with a free hydroxyl group . This action is directly opposite to that of phosphorylases and kinases, which attach phosphate groups to their...
, forming a four-layer alpha-beta-beta-alpha sandwich, unlike the more usual five-layered alpha-beta-alpha-beta-alpha arrangement. The arrangement of the catalytic side chain
Side chain
In organic chemistry and biochemistry, a side chain is a chemical group that is attached to a core part of the molecule called "main chain" or backbone. The placeholder R is often used as a generic placeholder for alkyl group side chains in chemical structure diagrams. To indicate other non-carbon...
s and metal ligands was found to be consistent with the three-metal ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
assisted catalysis mechanism proposed for other FBPases.
The fructose 1,6-bisphosphatases found within the Firmicutes
Firmicutes
The Firmicutes are a phylum of bacteria, most of which have Gram-positive cell wall structure. A few, however, such as Megasphaera, Pectinatus, Selenomonas and Zymophilus, have a porous pseudo-outer-membrane that causes them to stain Gram-negative...
(low GC Gram-positive
Gram-positive
Gram-positive bacteria are those that are stained dark blue or violet by Gram staining. This is in contrast to Gram-negative bacteria, which cannot retain the crystal violet stain, instead taking up the counterstain and appearing red or pink...
bacteria) do not show any significant sequence
Sequence (biology)
A sequence in biology is the one-dimensional ordering of monomers, covalently linked within in a biopolymer; it is also referred to as the primary structure of the biological macromolecule.-See also:* Protein sequence* DNA sequence...
similarity to the enzymes from other organism
Organism
In biology, an organism is any contiguous living system . In at least some form, all organisms are capable of response to stimuli, reproduction, growth and development, and maintenance of homoeostasis as a stable whole.An organism may either be unicellular or, as in the case of humans, comprise...
s. The Bacillus subtilis
Bacillus subtilis
Bacillus subtilis, known also as the hay bacillus or grass bacillus, is a Gram-positive, catalase-positive bacterium commonly found in soil. A member of the genus Bacillus, B. subtilis is rod-shaped, and has the ability to form a tough, protective endospore, allowing the organism to tolerate...
enzyme is inhibited by AMP
Adenosine monophosphate
Adenosine monophosphate , also known as 5'-adenylic acid, is a nucleotide that is used as a monomer in RNA. It is an ester of phosphoric acid and the nucleoside adenosine. AMP consists of a phosphate group, the sugar ribose, and the nucleobase adenine...
, though this can be overcome by phosphoenolpyruvate
Phosphoenolpyruvate
Phosphoenolpyruvic acid , or phosphoenolpyruvate as the anion, is an important chemical compound in biochemistry. It has the high-energy phosphate bond found in living organisms, and is involved in glycolysis and gluconeogenesis...
, and is dependent on Mn(2+). Mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
s lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as malate
Malate
Malate is the ionized form of malic acid. It is an important chemical compound in biochemistry. In the C4 carbon fixation process, malate is a source of CO2 in the Calvin cycle....
and glycerol
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
.
See also
- Fructose bisphosphatase deficiencyFructose bisphosphatase deficiencyIn Fructose bisphosphatase deficiency, there is not enough fructose bisphosphatase for gluconeogenesis to occur correctly. Glycolysis will still work, as it does not use this enzyme.-Presentation:...
- FructoseFructoseFructose, or fruit sugar, is a simple monosaccharide found in many plants. It is one of the three dietary monosaccharides, along with glucose and galactose, that are absorbed directly into the bloodstream during digestion. Fructose was discovered by French chemist Augustin-Pierre Dubrunfaut in 1847...
- GluconeogenesisGluconeogenesisGluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
- MetabolismMetabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...