Glucose-1,6-bisphosphate synthase
Encyclopedia
Glucose-1,6-bisphosphate synthase is a type of enzyme called a phosphotransferase
and is involved in mammalian starch and sucrose metabolism (KEGG, 2.7.1.106). It catalyzes the transfer of a phosphate
group from 1,3-bisphosphoglycerate
to glucose-1-phosphate
, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate
.
(image courtesy of the BRENDA enzyme database)
The enzyme requires a divalent metal ion cofactor. Zinc
2+, Magnesium
2+, Manganese
2+, Calcium
2+, Nickel
2+, Copper
2+, Cadmium
2+ are all proven effective cofactors. Additionally, the enzyme appears to function optimally in a pH range from 7.3-8.7 and at a temperature of 25 degrees Celsius.
1. inhibition of hexokinase
, an enzyme used in the first step of glycolysis.
2. activation of phosphofructokinase-1 (PFK-1) and pyruvate kinase
, both of which are enzymes involved in activation of the glycolytic pathway.
3. acts as a coenzyme for phosphoglucomutase
in glycolysis
and gluconeogenesis
.
4. acts as a cofactor for phosphopentomutase, which produces D-ribose-5-phosphate.
5. acts as a phosphate donor molecule for unknown nonmetabolic effector proteins.
6. increases in concentration during skeletal muscle
contraction.
7. dephosphorylation yields glucose-6-phosphate
, which is an important precursor molecule in glycolysis and the pentose phosphate pathway
.
Glucose-1,6-bisphosphate is most likely used in correlation with gluconeolysis. The product’s inhibition of hexokinase and activation of PFK-1 and pyruvate kinase is indicative of its role in glycolysis. Glucose-1,6-bisphosphate inhibit hexokinase stopping the production glucose-6-phosphate from D-glucose
. Its activation of PFK-1 and pyruvate kinase shows that glycolysis still continues without the production of glucose-6-phosphate from D-glucose. This means that the glucose-6-phosphate needed for glycolysis most likely comes from gluconeolysis.
The reactant glucose-1-phosphate is produced by gluconeolysis. This reactant can also form D-glucose-6-phosphate, which is needed for glycolysis. It can therefore be inferred that it is possible when glucose-1-phosphate is produced, it makes glucose-1,6-bisphosphate (with glucose-1,6-bisophosphate synthase) and glucose-6-phosphate. The glucose-1,6-bisphosphate increase the activity of glycolysis, of which glucose-6-phosphate is a reagent.
In addition, one of the reactants (1,3-bisphosphoglycerate
) and one of the products
(3-phosphoglycerate) are intermediates in the 'payoff' phase of glycolysis. In other words, two molecules involved with glucose-1,6-bisphosphate synthase are able to be both created and recycled in the glycolytic pathway.
The reactant glucose 1-phosphate is an important precursor molecule in
many different pathways, including glycolysis, gluconeogenesis and
the pentose phosphate pathway.
, lithium
, phosphoenolpyruvate
(PEP), and acetyl CoA.
The inhibition of the enzyme by fructose-1,6-bisphosphate is most likely a feedback inhibition due to the product of the enzyme (glucose-1,6-bisphosphate) activation of PFK-1 (the enzyme which produces fructose-1,6-bisphophate). When too much fructose-1,6-bisphosphate is produced, it inhibited the production of more PFK-1 activator.
The enzyme is also inhibited by PEP, which is a reagent of pyruvate kinase. The product of glucose-1,6-bisphosphate synthase (glucose-1,6-bisphosphate) activates pyruvate kinase.
Glucose-1,6-bisphosphate synthase appears to be activated by the presence of one of its substrates: 1,3-bisphosphoglycerate (glycerate-1,3-bisphosphate).
. Both enzymes contain serine
linked phosphates in their active sites, both have the same molecular weights, and both require a metal ion cofactor
. Perhaps most importantly, both enzymes produce glucose-1,6-bisphosphate as either a product or an intermediate.
http://www.genome.jp/dbget-bin/show_pathway?map00500+2.7.1.106
BRENDA enzyme database link for glucose-1,6-bisphosphate synthase (EC# 2.7.1.106)
http://www.brenda.uni-koeln.de/php/result_flat.php4?ecno=2.7.1.106
Structure of phosphoglucomutase in the protein data bank
http://www.rcsb.org/pdb/explore.do?structureId=1LXT
Phosphotransferase
Phosphotransferases are a category of enzymes that catalyze phosphorylation reactions. The general form of the reactions they catalyze is: A—P + B ⇔ B—P + A...
and is involved in mammalian starch and sucrose metabolism (KEGG, 2.7.1.106). It catalyzes the transfer of a phosphate
Phosphate
A phosphate, an inorganic chemical, is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry and biogeochemistry or ecology. Inorganic phosphates are mined to obtain phosphorus for use in...
group from 1,3-bisphosphoglycerate
1,3-Bisphosphoglycerate
1,3-Bisphosphoglyceric acid is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycle during photosynthesis...
to glucose-1-phosphate
Glucose-1-phosphate
Glucose 1-phosphate is a glucose molecule with a phosphate group on the 1'-carbon.-Catabolic:In glycogenolysis, it is the direct product of the reaction in which glycogen phosphorylase cleaves off a molecule of glucose from a greater glycogen structure.To be utilized in cellular catabolism it must...
, yielding 3-phosphoglycerate and glucose-1,6-bisphosphate
Glucose-1,6-bisphosphate
Glucose-1,6-bisphosphate is a derivative of glucose 1-phosphate....
.
(image courtesy of the BRENDA enzyme database)
The enzyme requires a divalent metal ion cofactor. Zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
2+, Magnesium
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+, Manganese
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+, Calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...
2+, Nickel
Nickel
Nickel is a chemical element with the chemical symbol Ni and atomic number 28. It is a silvery-white lustrous metal with a slight golden tinge. Nickel belongs to the transition metals and is hard and ductile...
2+, Copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
2+, Cadmium
Cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, bluish-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Similar to zinc, it prefers oxidation state +2 in most of its compounds and similar to mercury it shows a low...
2+ are all proven effective cofactors. Additionally, the enzyme appears to function optimally in a pH range from 7.3-8.7 and at a temperature of 25 degrees Celsius.
Metabolic Significance of the Catalyzed Reaction
The main product, glucose-1,6-bisphosphate, appears to have several functions:1. inhibition of hexokinase
Hexokinase
A hexokinase is an enzyme that phosphorylates a six-carbon sugar, a hexose, to a hexose phosphate. In most tissues and organisms, glucose is the most important substrate of hexokinases, and glucose-6-phosphate the most important product....
, an enzyme used in the first step of glycolysis.
2. activation of phosphofructokinase-1 (PFK-1) and pyruvate kinase
Pyruvate kinase
Pyruvate kinase is an enzyme involved in glycolysis. It catalyzes the transfer of a phosphate group from phosphoenolpyruvate to ADP, yielding one molecule of pyruvate and one molecule of ATP.-Reaction:The reaction with pyruvate kinase:...
, both of which are enzymes involved in activation of the glycolytic pathway.
3. acts as a coenzyme for phosphoglucomutase
Phosphoglucomutase
Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1' to the 6' position in the forward direction or the 6' to the 1' position in the reverse direction....
in glycolysis
Glycolysis
Glycolysis is the metabolic pathway that converts glucose C6H12O6, into pyruvate, CH3COCOO− + H+...
and 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....
.
4. acts as a cofactor for phosphopentomutase, which produces D-ribose-5-phosphate.
5. acts as a phosphate donor molecule for unknown nonmetabolic effector proteins.
6. increases in concentration during skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
contraction.
7. dephosphorylation yields glucose-6-phosphate
Glucose-6-phosphate
Glucose 6-phosphate is glucose sugar phosphorylated on carbon 6. This compound is very common in cells as the vast majority of glucose entering a cell will become phosphorylated in this way....
, which is an important precursor molecule in glycolysis and the pentose phosphate pathway
Pentose phosphate pathway
The pentose phosphate pathway is a process that generates NADPH and pentoses . There are two distinct phases in the pathway. The first is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of 5-carbon sugars...
.
Glucose-1,6-bisphosphate is most likely used in correlation with gluconeolysis. The product’s inhibition of hexokinase and activation of PFK-1 and pyruvate kinase is indicative of its role in glycolysis. Glucose-1,6-bisphosphate inhibit hexokinase stopping the production glucose-6-phosphate from D-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...
. Its activation of PFK-1 and pyruvate kinase shows that glycolysis still continues without the production of glucose-6-phosphate from D-glucose. This means that the glucose-6-phosphate needed for glycolysis most likely comes from gluconeolysis.
The reactant glucose-1-phosphate is produced by gluconeolysis. This reactant can also form D-glucose-6-phosphate, which is needed for glycolysis. It can therefore be inferred that it is possible when glucose-1-phosphate is produced, it makes glucose-1,6-bisphosphate (with glucose-1,6-bisophosphate synthase) and glucose-6-phosphate. The glucose-1,6-bisphosphate increase the activity of glycolysis, of which glucose-6-phosphate is a reagent.
In addition, one of the reactants (1,3-bisphosphoglycerate
1,3-Bisphosphoglycerate
1,3-Bisphosphoglyceric acid is a 3-carbon organic molecule present in most, if not all, living organisms. It primarily exists as a metabolic intermediate in both glycolysis during respiration and the Calvin cycle during photosynthesis...
) and one of the products
(3-phosphoglycerate) are intermediates in the 'payoff' phase of glycolysis. In other words, two molecules involved with glucose-1,6-bisphosphate synthase are able to be both created and recycled in the glycolytic pathway.
The reactant glucose 1-phosphate is an important precursor molecule in
many different pathways, including glycolysis, gluconeogenesis and
the pentose phosphate pathway.
Regulation of the Enzyme
Glucose-1,6-bisphosphate synthase is allosterically inhibited by inorganic phosphate, fructose-1,6-bisphosphate, 3-phosphoglycerate (a product), citrateCitrate
A citrate can refer either to the conjugate base of citric acid, , or to the esters of citric acid. An example of the former, a salt is trisodium citrate; an ester is triethyl citrate.-Other citric acid ions:...
, lithium
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...
, 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...
(PEP), and acetyl CoA.
The inhibition of the enzyme by fructose-1,6-bisphosphate is most likely a feedback inhibition due to the product of the enzyme (glucose-1,6-bisphosphate) activation of PFK-1 (the enzyme which produces fructose-1,6-bisphophate). When too much fructose-1,6-bisphosphate is produced, it inhibited the production of more PFK-1 activator.
The enzyme is also inhibited by PEP, which is a reagent of pyruvate kinase. The product of glucose-1,6-bisphosphate synthase (glucose-1,6-bisphosphate) activates pyruvate kinase.
Glucose-1,6-bisphosphate synthase appears to be activated by the presence of one of its substrates: 1,3-bisphosphoglycerate (glycerate-1,3-bisphosphate).
Enzyme Structure
No structure determination of glucose-1,6-bisphosphate synthase has been documented to date. Nevertheless, studies have shown that its structure appears to be markedly similar to a related enzyme called phosphoglucomutasePhosphoglucomutase
Phosphoglucomutase is an enzyme that transfers a phosphate group on an α-D-glucose monomer from the 1' to the 6' position in the forward direction or the 6' to the 1' position in the reverse direction....
. Both enzymes contain serine
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:...
linked phosphates in their active sites, both have the same molecular weights, and both require a metal ion cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
. Perhaps most importantly, both enzymes produce glucose-1,6-bisphosphate as either a product or an intermediate.
Relevant Links
KEGG: starch and sucrose metabolism with glucose-1,6-bisphosphate synthase (EC# 2.7.1.106)http://www.genome.jp/dbget-bin/show_pathway?map00500+2.7.1.106
BRENDA enzyme database link for glucose-1,6-bisphosphate synthase (EC# 2.7.1.106)
http://www.brenda.uni-koeln.de/php/result_flat.php4?ecno=2.7.1.106
Structure of phosphoglucomutase in the protein data bank
http://www.rcsb.org/pdb/explore.do?structureId=1LXT