Glucose-1,6-bisphosphate synthase

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

3. It acts as a coenzyme for phosphoglucomutase in glycolysis and gluconeogenesis.

4. It 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. It increases in concentration during skeletal muscle contraction.

7. Its 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.

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.

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-bisphosphate). 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 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.

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

References

References

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2. (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..
3. (December 1986). "Changes in glucose 1,6-bisphosphate content in rat skeletal muscle during contraction". Biochem. J..
4. (February 1988). "Distribution of the glucose-1,6-bisphosphate system in brain and retina". J. Neurochem..
5. (March 1989). "Transient increase in glucose 1,6-bisphosphate in human skeletal muscle during isometric contraction". Biochem. J..
6. Cowgill RW. (December 1959). "Lobster muscle phosphorylase: purification and properties". J. Biol. Chem..
7. (September 1964). "PHOSPHOGLUCOMUTASE. I. PURIFICATION AND PROPERTIES OF PHOSPHOGLUCOMUTASE FROM ESCHERICHIA COLI". J. Biol. Chem..
8. (June 1977). "Inhibitors of glucose-1,6-bisphosphate synthase". J. Biol. Chem..