Glucose-1,6-bisphosphate synthase

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 (Rose, et. al, 1975). ⁴

_{(image courtesy of the BRENDA enzyme database)}

The enzyme requires a divalent metal ion cofactor. Zinc 2+, Magnesium 2+, Manganese 2+, Calcium 2+, Nickle 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 (Rose, et. al, 1975). ⁴

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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 (Piatti, 1992)³.

2. activation of phosphofructokinase-1 (PFK-1) and pyruvate kinase, both of which are enzymes involved in activation of the glycolytic pathway (Bassols, et. al, 1986 ¹ and Piatti, et. al, 1992 ³).

3. acts as a coenzyme for phosphoglucomutase in glycolysis and gluconeogenesis (Yip, et. al, 1988)⁷

4. acts as a cofactor for phosphopentomutase, which produces D-ribose-5-phosphate (Kammen, et. al, 1969)⁸.

5. acts as a phosphate donor molecule for unknown nonmetabolic effector proteins (Yip, et. al, 1988)⁷.

6. increases in concentration during skeletal muscle contraction (Lee and Katz, 1989)².

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 (COWGILL RW, 1959)⁹. This reactant can also form D-glucose-6-phosphate, (Joshi JG et. al, 1964)¹⁰ 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 (Rose, et. al, 1975⁴ and 1977⁵).

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) (Lee, et. al, 1989)².

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 (Rose, et. al, 1977⁵).

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

1. A M Bassols, J Carreras, and R Cussó. “Changes in glucose 1,6-bisphosphate content in rat skeletal muscle during contraction.” Biochem J. 1986 December 15; 240(3): 747–751.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1147482

2. A D Lee and A Katz. “Transient increase in glucose 1,6-bisphosphate in human skeletal muscle during isometric contraction.” Biochem J. 1989 March 15; 258(3): 915–918.
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1138452

3. Piatti E, Accorsi A, Piacentini MP, Fazi A. “Glucose 1,6-bisphosphate-overloaded erythrocytes: a strategy to investigate the metabolic role of the bisphosphate in red blood cells.” Arch Biochem Biophys. 1992 Feb 14;293(1):117-21.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=1309980&itool=iconabstr&query_hl=1&itool=pubmed_docsum

4. Rose IA, Warms JV, Kaklij G. “A specific enzyme for glucose 1,6-bisphosphate synthesis.” J Biol Chem. 1975 May 10;250(9):3466-70.
http://www.brenda.uni-koeln.de/literature/lit.php4?e=2.7.1.106&r=640348

5. Rose IA, Warms JV, Wong LJ. “Inhibitors of glucose-1,6-bisphosphate synthase.” J Biol Chem. 1977 Jun 25;252(12):4262-8.
http://www.brenda.uni-koeln.de/literature/lit.php4?e=2.7.1.106&r=640350

6. Ueda M, Hirose M, Sasaki R, Chiba H. “Regulation of glucose 1,6-bisphosphate level in liver. III. Purification and properties of bovine glucose 1,6-bisphosphate synthase.” J Biochem (Tokyo). 1978 Jun;83(6):1721-30.
http://www.brenda.uni-koeln.de/literature/lit.php4?e=2.7.1.106&r=640349

7. Yip V, Pusateri ME, Carter J, Rose IA, Lowry OH. “Distribution of the glucose-1,6-bisphosphate system in brain and retina.” J Neurochem. 1988 Feb;50(2):594-602.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2826701&dopt=Abstract

8. Kammen HO, Koo R. “Phosphopentomutases. I. Identification of two activities in rabbit tissues.” J. Biol. Chem. 244 (1969) 4888-93.
http://www.genome.jp/dbget-bin/www_bget?medline+5824563

9. COWGILL RW. “Lobster muscle phosphorylase: purification and properties.” J. Biol. Chem. 234 (1959) 3146-53.
http://www.genome.jp/dbget-bin/www_bget?medline+13812491

10. JOSHI JG, HANDLER P. “PHOSPHOGLUCOMUTASE. I. PURIFICATION AND PROPERTIES OF PHOSPHOGLUCOMUTASE FROM ESCHERICHIA COLI.” J. Biol. Chem. 239 (1964) 2741-51.
http://www.genome.jp/dbget-bin/www_bget?medline+14216423