Glucose-1,6-bisphosphate synthase


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, [http://www.brenda.uni-koeln.de/php/result_flat.php4?ecno=2.7.1.106 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.cite journal |author=Rose IA, Warms JV, Kaklij G |title=A specific enzyme for glucose 1,6-bisphosphate synthesis |journal=J. Biol. Chem. |volume=250 |issue=9 |pages=3466–70 |year=1975 |month=May |pmid=235548 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=235548]

(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.

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.cite journal |author=Piatti E, Accorsi A, Piacentini MP, Fazi A |title=Glucose 1,6-bisphosphate-overloaded erythrocytes: a strategy to investigate the metabolic role of the bisphosphate in red blood cells |journal=Arch. Biochem. Biophys. |volume=293 |issue=1 |pages=117–21 |year=1992 |month=Feb |pmid=1309980 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/0003-9861(92)90373-5]

2. activation of phosphofructokinase-1 (PFK-1) and pyruvate kinase, both of which are enzymes involved in activation of the glycolytic pathway. [cite journal |author=Bassols AM, Carreras J, Cussó R |title=Changes in glucose 1,6-bisphosphate content in rat skeletal muscle during contraction |journal=Biochem. J. |volume=240 |issue=3 |pages=747–51 |year=1986 |month=Dec |pmid=3827864 |pmc=1147482 |doi= |url=]

3. acts as a coenzyme for phosphoglucomutase in glycolysis and gluconeogenesis.cite journal |author=Yip V, Pusateri ME, Carter J, Rose IA, Lowry OH |title=Distribution of the glucose-1,6-bisphosphate system in brain and retina |journal=J. Neurochem. |volume=50 |issue=2 |pages=594–602 |year=1988 |month=Feb |pmid=2826701 |doi= |url=]

4. acts as a cofactor for phosphopentomutase, which produces D-ribose-5-phosphate. [cite journal |author=Kammen HO, Koo R |title=Phosphopentomutases. I. Identification of two activities in rabbit tissues |journal=J. Biol. Chem. |volume=244 |issue=18 |pages=4888–93 |year=1969 |month=Sep |pmid=5824563 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=5824563] 5. acts as a phosphate donor molecule for unknown nonmetabolic effector proteins.

6. increases in concentration during skeletal muscle contraction.cite journal |author=Lee AD, Katz A |title=Transient increase in glucose 1,6-bisphosphate in human skeletal muscle during isometric contraction |journal=Biochem. J. |volume=258 |issue=3 |pages=915–8 |year=1989 |month=Mar |pmid=2730576 |pmc=1138452 |doi= |url=] 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. [cite journal |author=Cowgill RW |title=Lobster muscle phosphorylase: purification and properties |journal=J. Biol. Chem. |volume=234 |issue= |pages=3146–53 |year=1959 |month=Dec |pmid=13812491 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=13812491] This reactant can also form D-glucose-6-phosphate, [cite journal |author=Joshi JG, Handler P |title=PHOSPHOGLUCOMUTASE. I. PURIFICATION AND PROPERTIES OF PHOSPHOGLUCOMUTASE FROM ESCHERICHIA COLI |journal=J. Biol. Chem. |volume=239 |issue= |pages=2741–51 |year=1964 |month=Sep |pmid=14216423 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=14216423] 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 inmany different pathways, including glycolysis, gluconeogenesis andthe 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-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 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.cite journal |author=Rose IA, Warms JV, Wong LJ |title=Inhibitors of glucose-1,6-bisphosphate synthase |journal=J. Biol. Chem. |volume=252 |issue=12 |pages=4262–8 |year=1977 |month=Jun |pmid=558982 |doi= |url=http://www.jbc.org/cgi/pmidlookup?view=long&pmid=558982]

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

*cite journal |author=Ueda M, Hirose M, Sasaki R, Chiba H |title=Regulation of glucose 1,6-bisphosphate level in liver. III. Purification and properties of bovine glucose 1,6-bisphosphate synthase |journal=J. Biochem. |volume=83 |issue=6 |pages=1721–30 |year=1978 |month=Jun |pmid=670163 |doi= |url=http://jb.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=670163


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