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

(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]


Metabolic Significance of the Catalyzed Reaction

The main product, glucose-1,6-bisphosphate, appears to have several functions:

1. inhibition of hexokinase, an enzyme used in the first step of glycolysis.[2]

2. activation of phosphofructokinase-1 (PFK-1) and pyruvate kinase, both of which are enzymes involved in activation of the glycolytic pathway.[2][3]

3. acts as a coenzyme for phosphoglucomutase in glycolysis and gluconeogenesis.[4]

4. acts as a cofactor for phosphopentomutase, which produces D-ribose-5-phosphate.[5] 5. acts as a phosphate donor molecule for unknown nonmetabolic effector proteins.[4]

6. increases in concentration during skeletal muscle contraction.[6]

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.[7] This reactant can also form D-glucose-6-phosphate,[8] 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.

Regulation of the Enzyme

Glucose-1,6-bisphosphate synthase is allosterically inhibited by inorganic phosphate, fructose-1,6-bisphosphate, 3-phosphoglycerate (a product), citrate, lithium, phosphoenolpyruvate (PEP), and acetyl CoA.[1][9]

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).[6]

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 phosphoglucomutase. 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.[9]

Relevant Links

KEGG: starch and sucrose metabolism with glucose-1,6-bisphosphate synthase (EC#

BRENDA enzyme database link for glucose-1,6-bisphosphate synthase (EC#

Structure of phosphoglucomutase in the protein data bank


  1. ^ a b c Rose IA, Warms JV, Kaklij G (May 1975). "A specific enzyme for glucose 1,6-bisphosphate synthesis". J. Biol. Chem. 250 (9): 3466–70. PMID 235548.  
  2. ^ a b Piatti E, Accorsi A, Piacentini MP, Fazi A (February 1992). "Glucose 1,6-bisphosphate-overloaded erythrocytes: a strategy to investigate the metabolic role of the bisphosphate in red blood cells". Arch. Biochem. Biophys. 293 (1): 117–21. doi:10.1016/0003-9861(92)90373-5. PMID 1309980.  
  3. ^ Bassols AM, Carreras J, Cussó R (December 1986). "Changes in glucose 1,6-bisphosphate content in rat skeletal muscle during contraction". Biochem. J. 240 (3): 747–51. PMID 3827864.  
  4. ^ a b Yip V, Pusateri ME, Carter J, Rose IA, Lowry OH (February 1988). "Distribution of the glucose-1,6-bisphosphate system in brain and retina". J. Neurochem. 50 (2): 594–602. doi:10.1111/j.1471-4159.1988.tb02952.x. PMID 2826701.  
  5. ^ Kammen HO, Koo R (September 1969). "Phosphopentomutases. I. Identification of two activities in rabbit tissues". J. Biol. Chem. 244 (18): 4888–93. PMID 5824563.  
  6. ^ a b Lee AD, Katz A (March 1989). "Transient increase in glucose 1,6-bisphosphate in human skeletal muscle during isometric contraction". Biochem. J. 258 (3): 915–8. PMID 2730576.  
  7. ^ Cowgill RW (December 1959). "Lobster muscle phosphorylase: purification and properties". J. Biol. Chem. 234: 3146–53. PMID 13812491.  
  9. ^ a b Rose IA, Warms JV, Wong LJ (June 1977). "Inhibitors of glucose-1,6-bisphosphate synthase". J. Biol. Chem. 252 (12): 4262–8. PMID 558982.  


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