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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 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 verte ...
and the Calvin cycle, which are both anabolic pathways: :D-fructose 1,6-bisphosphate + H2O = D-fructose 6-phosphate + phosphate Phosphofructokinase (EC 2.7.1.11) catalyses the reverse conversion of fructose 6-phosphate to fructose-1,6-bisphosphate, but this is not just the reverse reaction, because the co-substrates are different (and so thermodynamic requirements are not violated). The two enzymes each catalyse the conversion in one direction only, and are regulated by metabolites such as fructose 2,6-bisphosphate so that high activity of one of them is accompanied by low activity of the other. More specifically, fructose 2,6-bisphosphate allosterically inhibits fructose 1,6-bisphosphatase, but activates phosphofructokinase-I. Fructose 1,6-bisphosphatase is involved in many different
metabolic pathways In biochemistry, a metabolic pathway is a linked series of chemical reactions occurring within a cell. The reactants, products, and intermediates of an enzymatic reaction are known as metabolites, which are modified by a sequence of chemical ...
and found in most
organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...
s. FBPase requires metal ions for catalysis ( Mg2+ and Mn2+ being preferred) and the enzyme is potently inhibited by Li+.


Structure

The fold of fructose-1,6-bisphosphatase from
pigs The pig (''Sus domesticus''), also called swine (: swine) or hog, is an omnivorous, domesticated, even-toed, hoofed mammal. It is named the domestic pig when distinguishing it from other members of the genus '' Sus''. Some authorities cons ...
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 BIND () is a suite of software for interacting with the Domain Name System (DNS). Its most prominent component, named (pronounced ''name-dee'': , short for ''name Daemon (computing), daemon''), performs both of the main DNS server roles, acting ...
metal
ions An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
and participate in catalysis. This motif is also found in the distantly-related
fungal A fungus (: fungi , , , or ; or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as one of the tradit ...
,
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
l and
yeast Yeasts are eukaryotic, single-celled microorganisms classified as members of the fungus kingdom (biology), kingdom. The first yeast originated hundreds of millions of years ago, and at least 1,500 species are currently recognized. They are est ...
IMPase homologues. It has been suggested that these
protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
s define an ancient structurally conserved family involved in diverse
metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...
pathways, including inositol signalling, gluconeogenesis, sulphate assimilation and possibly
quinone The quinones are a class of organic compounds that are formally "derived from aromatic compounds benzene.html" ;"title="uch as benzene">uch as benzene or naphthalene] by conversion of an even number of –CH= groups into –C(=O)– groups with ...
metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...
.


Species distribution

Three different groups of FBPases have been identified in
eukaryotes The eukaryotes ( ) constitute the domain of Eukaryota or Eukarya, organisms whose cells have a membrane-bound nucleus. All animals, plants, fungi, seaweeds, and many unicellular organisms are eukaryotes. They constitute a major group of ...
and
bacteria Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one Cell (biology), biological cell. They constitute a large domain (biology), domain of Prokaryote, prokaryotic microorganisms. Typically a few micr ...
(FBPase I-III). None of these groups have been found in
Archaea Archaea ( ) is a Domain (biology), domain of organisms. Traditionally, Archaea only included its Prokaryote, prokaryotic members, but this has since been found to be paraphyletic, as eukaryotes are known to have evolved from archaea. Even thou ...
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 A thermophile is a type of extremophile that thrives at relatively high temperatures, between . Many thermophiles are archaea, though some of them are bacteria and fungi. Thermophilic eubacteria are suggested to have been among the earliest bact ...
archaea and the hyperthermophilic
bacterium Bacteria (; : bacterium) are ubiquitous, mostly free-living organisms often consisting of one biological cell. They constitute a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria were among the ...
'' 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 An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...
s. A structural study suggests that FBPase V has a novel fold for a
sugar Sugar is the generic name for sweet-tasting, soluble carbohydrates, many of which are used in food. Simple sugars, also called monosaccharides, include glucose Glucose is a sugar with the Chemical formula#Molecular formula, molecul ...
phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid Ester, monoester into a phosphate ion and an Alcohol (chemistry), alcohol. Because a phosphatase enzyme catalysis, catalyzes the hydrolysis of its Substrate ...
, 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 Catalysis () is the increase in reaction rate, rate of a chemical reaction due to an added substance known as a catalyst (). Catalysts are not consumed by the reaction and remain unchanged after it. If the reaction is rapid and the catalyst ...
side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
s and metal
ligands In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's ...
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 ''
Bacillota The Bacillota (synonym Firmicutes) are a phylum of bacteria, most of which have Gram-positive cell wall structure. They have round cells, called cocci (singular coccus), or rod-like forms (bacillus). A few Bacillota, such as '' Megasphaera'', ...
'' (low GC
Gram-positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. The Gram stain is ...
bacteria) do not show any significant
sequence In mathematics, a sequence is an enumerated collection of objects in which repetitions are allowed and order matters. Like a set, it contains members (also called ''elements'', or ''terms''). The number of elements (possibly infinite) is cal ...
similarity to the
enzymes An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as pro ...
from other
organism An organism is any life, living thing that functions as an individual. Such a definition raises more problems than it solves, not least because the concept of an individual is also difficult. Many criteria, few of them widely accepted, have be ...
s. The ''
Bacillus subtilis ''Bacillus subtilis'' (), known also as the hay bacillus or grass bacillus, is a gram-positive, catalase-positive bacterium, found in soil and the gastrointestinal tract of ruminants, humans and marine sponges. As a member of the genus ''Bacill ...
'' enzyme is inhibited by AMP, though this can be overcome by
phosphoenolpyruvate Phosphoenolpyruvate (2-phosphoenolpyruvate, PEP) is the carboxylic acid derived from the enol of pyruvate and a phosphate anion. It exists as an anion. PEP is an important intermediate in biochemistry. It has the high-energy phosphate, highest-e ...
, and is dependent on Mn(2+).
Mutant In biology, and especially in genetics, a mutant is an organism or a new genetic character arising or resulting from an instance of mutation, which is generally an alteration of the DNA sequence of the genome or chromosome of an organism. It i ...
s lacking this enzyme are apparently still able to grow on gluconeogenic growth substrates such as
malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...
and
glycerol Glycerol () is a simple triol compound. It is a colorless, odorless, sweet-tasting, viscous liquid. The glycerol backbone is found in lipids known as glycerides. It is also widely used as a sweetener in the food industry and as a humectant in pha ...
. Image:Beta-D-fructose-1,6-bisphosphate wpmp.png , Fructose 1,6-bisphosphate Image:Beta-D-fructose-6-phosphate wpmp.png , Fructose 6-phosphate


Interactive pathway map


Hibernation and cold adaptation

Fructose 1,6-bisphosphatase also plays a key role in
hibernation Hibernation is a state of minimal activity and metabolic reduction entered by some animal species. Hibernation is a seasonal heterothermy characterized by low body-temperature, slow breathing and heart-rate, and low metabolic rate. It is mos ...
, which requires strict regulation of
metabolic Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the ...
processes to facilitate entry into hibernation, maintenance, arousal from hibernation, and adjustments to allow long-term
dormancy Dormancy is a period in an organism's Biological life cycle, life cycle when growth, development, and (in animals) physical activity are temporarily stopped. This minimizes metabolism, metabolic activity and therefore helps an organism to conserv ...
. During hibernation, an animal's metabolic rate may decrease to around 1/25 of its euthermic resting metabolic rate. FBPase is modified in hibernating animals to be much more temperature sensitive than it is in euthermic animals. FBPase in the liver of a hibernating bat showed a 75% decrease in Km for its substrate FBP at 5 °C than at 37 °C. However, in a euthermic bat this decrease was only 25%, demonstrating the difference in temperature sensitivity between hibernating and euthermic bats. When sensitivity to allosteric inhibitors such as AMP, ADP, inorganic phosphate, and fructose-2,6-bisphosphate were examined, FBPase from hibernating bats was much more sensitive to inhibitors at low temperature than in euthermic bats. During hibernation, respiration also dramatically decreases, resulting in conditions of relative anoxia in the tissues. Anoxic conditions inhibit
gluconeogenesis 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 verte ...
, and therefore FBPase, while stimulating
glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...
, and this is another reason for reduced FBPase activity in hibernating animals. The substrate of FBPase, fructose 1,6-bisphosphate, has also been shown to activate pyruvate kinase in glycolysis, linking increased glycolysis to decreased gluconeogenesis when FBPase activity is decreased during hibernation. In addition to hibernation, there is evidence that FBPase activity varies significantly between warm and cold seasons even for animals that do not hibernate. In rabbits exposed to cold temperatures, FBPase activity decreased throughout the duration of cold exposure, increasing when temperatures became warmer again. The mechanism of this FBPase inhibition is thought to be digestion of FBPase by lysosomal
protease A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalysis, catalyzes proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the formation of new protein products ...
s, which are released at higher levels during colder periods. Inhibition of FBPase through proteolytic digestion decreases gluconeogenesis relative to glycolysis during cold periods, similar to hibernation. Fructose 1,6-bisphosphate aldolase is another temperature dependent enzyme that plays an important role in the regulation of glycolysis and gluconeogenesis during hibernation. Its main role is in glycolysis instead of gluconeogenesis, but its substrate is the same as FBPase's, so its activity affects that of FBPase in gluconeogenesis. Aldolase shows similar changes in activity to FBPase at colder temperatures, such as an upward shift in optimum pH at colder temperatures. This adaptation allows enzymes such as FBPase and fructose-1,6-bisphosphate aldolase to track intracellular pH changes in hibernating animals and match their activity ranges to these shifts. Aldolase also complements the activity of FBPase in anoxic conditions (discussed above) by increasing glycolytic output while FBPase inhibition decreases gluconeogenesis activity.


Diabetes

Fructose 1,6-bisphosphatase is also a key player in treating
type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
. In this disease, hyperglycemia causes many serious problems, and treatments often focus on lowering blood sugar levels. Gluconeogenesis in the liver is a major cause of glucose overproduction in these patients, and so inhibition of gluconeogenesis is a reasonable way to treat type 2 diabetes. FBPase is a good enzyme to target in the gluconeogenesis pathway because it is rate-limiting and controls the incorporation of all three-carbon substrates into glucose but is not involved in glycogen breakdown and is removed from mitochondrial steps in the pathway. This means that altering its activity can have a large effect on gluconeogenesis while reducing the risk of
hypoglycemia Hypoglycemia (American English), also spelled hypoglycaemia or hypoglycæmia (British English), sometimes called low blood sugar, is a fall in blood sugar to levels below normal, typically below 70 mg/dL (3.9 mmol/L). Whipple's tria ...
and other potential side effects from altering other enzymes in gluconeogenesis. Drug candidates have been developed that mimic the inhibitory activity of AMP on FBPase. Efforts were made to mimic the allosteric inhibitory effects of AMP while making the drug as structurally different from it as possible. Second-generation FBPase inhibitors have now been developed and have had good results in clinical trials with non-human mammals and now humans.


See also

* Fructose bisphosphatase deficiency *
Fructose Fructose (), or fruit sugar, is a Ketose, ketonic monosaccharide, simple sugar found in many plants, where it is often bonded to glucose to form the disaccharide sucrose. It is one of the three dietary monosaccharides, along with glucose and gal ...
*
Gluconeogenesis 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 verte ...
*
Metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...


References


Further reading

*


External links

* {{Portal bar, Biology, border=no EC 3.1.3 Protein families