Glucose 6-phosphatase

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Glucose 6-phosphatase.
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EC no. 3.1.3.9
CAS no. 9001-39-2
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Glucose-6-phosphate Alpha-D-Glucospyranose-6-Phosphate.svg
Glucose-6-phosphate
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Glucose

The enzyme glucose 6-phosphatase (EC 3.1.3.9, G6Pase; systematic name D-glucose-6-phosphate phosphohydrolase) catalyzes the hydrolysis of glucose 6-phosphate, resulting in the creation of a phosphate group and free glucose:

Contents

D-glucose 6-phosphate + H2O = D-glucose + phosphate

Glucose is then exported from the cell via glucose transporter membrane proteins. [1] This catalysis completes the final step in gluconeogenesis and therefore plays a key role in the homeostatic regulation of blood glucose levels. [2]

Glucose 6-phosphatase is a complex of multiple component proteins, including transporters for G6P, glucose, and phosphate. The main phosphatase function is performed by the glucose 6-phosphatase catalytic subunit. In humans, there are three isozymes of the catalytic subunit: glucose 6-phosphatase-α, encoded by G6PC; IGRP, encoded by G6PC2; and glucose 6-phosphatase-β, encoded by G6PC3. [3]

Glucose 6-phosphatase-α and glucose 6-phosphatase-β are both functional phosphohydrolases, and have similar active site structure, topology, mechanism of action, and kinetic properties with respect to G6P hydrolysis. [4] In contrast, IGRP has almost no hydrolase activity, and may play a different role in stimulating pancreatic insulin secretion. [5]

Vanadium containing chloroperoxidase enzyme with amino acid residues shown in color. Vanadium containing chloroperoxidase has a similar structure and active site as glucose 6-phosphatase.(From pdb 1IDQ) Wiki image (2).png
Vanadium containing chloroperoxidase enzyme with amino acid residues shown in color. Vanadium containing chloroperoxidase has a similar structure and active site as glucose 6-phosphatase.(From pdb 1IDQ)
Position of active site amino acid residues of vanadium containing chloroperoxidase shown in relation to enzyme surface.(From pdb 1IDQ) Final for wiki (1).png
Position of active site amino acid residues of vanadium containing chloroperoxidase shown in relation to enzyme surface.(From pdb 1IDQ)
The active site of vanadium containing chloroperoxidase. The residues Lys353, Arg360, Arg490, His404, and His496 correspond to Lys76, Arg83, Arg170, His119, and His176 in Glc 6-Pase. (From pdb 1IDQ) Final wiki 2.png
The active site of vanadium containing chloroperoxidase. The residues Lys353, Arg360, Arg490, His404, and His496 correspond to Lys76, Arg83, Arg170, His119, and His176 in Glc 6-Pase. (From pdb 1IDQ)

Structure and function

Although a clear consensus has not been reached, a large number of scientists adhere to a substrate-transport model to account for the catalytic properties of glucose 6-phosphatase. In this model, glucose 6-phosphatase has a low degree of selectivity. The transfer of the glucose 6-phosphate is carried out by a transporter protein (T1) and the endoplasmic reticulum (ER) contains structures allowing the exit of the phosphate group (T2) and glucose (T3). [6]

Glucose 6-phosphatase consists of 357 amino acids, and is anchored to the endoplasmic reticulum (ER) by nine transmembrane helices. Its N-terminal and active site are found on the lumen side of the ER and its C-terminus projects into the cytoplasm. Due to its tight association to the ER, the exact structure of glucose 6-phosphatase remains unknown. However, sequence alignment has shown that glucose 6-phosphatase is structurally similar to the active site of the vanadium-containing chloroperoxidase found in Curvularia inaequalis. [7]

Based on pH kinetic studies of glucose 6-phosphatase-α catalysis, it was proposed that the hydrolysis of glucose 6-phosphate was completed via a covalent phosphohistidine glucose 6-phosphate intermediate. The active site of glucose 6-phosphatase-α was initially identified by the presence of a conserved phosphate signature motif usually found in lipid phosphatases, acid phosphatases, and vanadium haloperoxidases. [4]

Essential residues in the active site of vanadium haloperoxidases include: Lys353, Arg360, Arg490, His404, and His496. Corresponding residues in the active site of glucose 6-phosphatase-α include Arg170 and Arg83, which donate hydrogen ions to the phosphate, stabilizing the transition state, His119, which provides a proton to the dephosphorylated oxygen attached to glucose, and His176, which completes a nucleophilic attack on the phosphate to form a covalently bound phosphoryl enzyme intermediate. [1] Within the Vanadium-containing chloroperoxidase, Lys353 was found to stabilize the phosphate in the transition state. However, the corresponding residue in glucose 6-phosphatase-α (Lys76) resides within the ER membrane and its function, if any, is currently undetermined. With the exception of Lys76, these residues are all located on the luminal side of the ER membrane. [4]

Glucose 6-phosphatase-β is a ubiquitously expressed, 346-amino acid membrane protein that shares 36% sequence identity with glucose 6-phosphatase-α. Within the glucose 6-phosphatase-β enzyme, sequence alignments predict that its active site contains His167, His114, and Arg79. Similar to that of the glucose 6-phosphatase-α active site, His167 is the residue that provides the nucleophilic attack, and His114, and Arg79 are the hydrogen donors. Glucose 6-phosphatase-β is also localized in the ER membrane, although its orientation is unknown. [4]

Mechanism

The hydrolysis of glucose 6-phosphate begins with a nucleophilic attack on the sugar-bound phosphate by His176 resulting in the formation of a phosphohistidine bond and the degradation of a carbonyl. A Negatively charged oxygen then transfers its electrons reforming a carbonyl and breaking its bond with glucose. The negatively charged glucose-bound oxygen is then protonated by His119 forming a free glucose. The phospho-intermediate produced by the reaction between His176 and the phosphate group is then broken by a hydrophilic attack; after the addition of another hydroxide and the decomposition of a carbonyl, the carbonyl is reformed kicking off the electrons originally donated by the His176 residue thereby creating a free phosphate group and completing the hydrolysis. [1]

Sdfh.gif

Expression

Genes coding for the enzyme are primarily expressed in the liver, in the kidney cortex and (to a lesser extent) in the β-cells of the pancreatic islets and intestinal mucosa (especially during times of starvation). [6] According to Surholt and Newsholme, glucose 6-phosphatase is present in a wide variety of muscles across the animal kingdom, albeit at very low concentrations. [8] Thus, the glycogen that muscles store is not usually available for the rest of the body's cells because glucose 6-phosphate cannot cross the sarcolemma unless it is dephosphorylated. The enzyme plays an important role during periods of fasting and when glucose levels are low. It has been shown that starvation and diabetes induces a two- to threefold increase in glucose 6-phosphatase activity in the liver. [6] Glc 6-Pase activity also increases dramatically at birth when an organism becomes independent of the mothers source of glucose. The human Glc 6-Pase gene contains five exons spanning approximately 125.5 kb DNA located on chromosome 17q21. [9]

Clinical significance

Mutations of the glucose 6-phosphatase system, to be specific the glucose 6-phosphatase-α subunit (glucose 6-phosphatase-α), glucose 6-transporter (G6PT), and glucose 6-phosphatase-β (glucose 6-phosphatase-β or G6PC3) subunits lead to deficiencies in the maintenance of interprandial glucose homeostasis and neutrophil function and homeostasis. [10] [11] Mutations in both glucose 6-phosphatase-α and G6PT lead to glycogen storage disease type I (GSD 1, von Gierke's disease). [12] To be specific, mutations in the glucose-6-phosphatase-α lead to Glycogen Storage Disease Type-1a, which is characterized by accumulation of glycogen and fat in the liver and kidneys, resulting in hepatomegaly and renomegaly. [13] GSD-1a constitutes approximately 80% of GSD-1 cases that present clinically. [14] Absence of G6PT leads to GSD-1b (GSD-1b), which is characterized by the lack of a G6PT and represents 20% of the cases that present clinically. [14] [15]

Breakdown of the various constituents of glucose 6-phosphatase system deficiency Hierarchy of Glucose-6-phosphatase system deficiency.png
Breakdown of the various constituents of glucose 6-phosphatase system deficiency

The specific cause of the GSD-1a stems from nonsense mutations, insertions/deletions with or without a shift in the reading frame, or splice site mutations that occur at the genetic level. [6] The missense mutations affect the two large luminal loops and transmembrane helices of glucose 6-phosphatase-α, abolishing or greatly reducing activity of the enzyme. [6] The specific cause of GSD-1b stems from "severe" mutations such as splice site mutations, frame-shifting mutations, and substitutions of a highly conserved residue that completely destroyed G6PT activity. [6] These mutations lead to the prevalence of GSD-1 by preventing the transport of glucose-6-phosphate (G6P) into the luminal portion of the ER and also inhibiting the conversion of G6P into glucose to be used by the cell.

The third type of glucose 6-phosphatase deficiency, glucose 6-phosphatase-β deficiency, is characterized by a congenital neutropenia syndrome in which neutrophils exhibit enhanced endoplasmic reticulum (ER) stress, increased apoptosis, impaired energy homeostasis, and impaired functionality. [16] It can also lead to cardiac and urogenital malformations. [17] This third class of deficiency is also affected by a G6PT deficiency as glucose-6-phosphatase-β also lies within the ER lumen and thus can lead to similar symptoms of glucose-6-phosphatase-β deficiency be associated with GSD-1b. [15] Furthermore, recent studies have elucidated this area of similarity between both deficiencies and have shown that aberrant glycosylation occurs in both deficiencies. [18] The neutrophil glycosylation has a profound effect on neutrophil activity and thus may also be classified as a congenital glycosylation disorder as well. [18]

The major function of glucose 6-phosphatase-β has been determined to provide recycled glucose to the cytoplasm of neutrophils in order maintain normal function. Disruption of the glucose to G6P ratio due to significant decrease intracellular glucose levels cause significant disruption of glycolysis and HMS. [11] Unless countered by uptake of extracellular glucose this deficiency leads to neutrophil dysfunction. [11]

Vanadium compounds such as vanadyl sulfate have been shown to inhibit the enzyme, and thus increase the insulin sensitivity in vivo in diabetics, as assessed by the hyperinsulinemic clamp technique, which may have potential therapeutic implications. [19] [20]

See also

Notes

Molecular graphics images were produced using UCSF Chimera. [21]

Related Research Articles

<span class="mw-page-title-main">Phosphorylation</span> Chemical process of introducing a phosphate

In biochemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology. Protein phosphorylation often activates many enzymes.

<span class="mw-page-title-main">Glycogen</span> Glucose polymer used as energy store in animals

Glycogen is a multibranched polysaccharide of glucose that serves as a form of energy storage in animals, fungi, and bacteria. It is the main storage form of glucose in the human body.

<span class="mw-page-title-main">Glycogenolysis</span> Breakdown of glycogen

Glycogenolysis is the breakdown of glycogen (n) to glucose-1-phosphate and glycogen (n-1). Glycogen branches are catabolized by the sequential removal of glucose monomers via phosphorolysis, by the enzyme glycogen phosphorylase.

<span class="mw-page-title-main">Phosphoglucomutase</span>

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.

<span class="mw-page-title-main">Glucose 6-phosphate</span> Chemical compound

Glucose 6-phosphate is a glucose sugar phosphorylated at the hydroxy group on carbon 6. This dianion is very common in cells as the majority of glucose entering a cell will become phosphorylated in this way.

<span class="mw-page-title-main">Glycogen phosphorylase</span> Class of enzymes

Glycogen phosphorylase is one of the phosphorylase enzymes. Glycogen phosphorylase catalyzes the rate-limiting step in glycogenolysis in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. Glycogen phosphorylase is also studied as a model protein regulated by both reversible phosphorylation and allosteric effects.

<span class="mw-page-title-main">Glucose 1-phosphate</span> Chemical compound

Glucose 1-phosphate is a glucose molecule with a phosphate group on the 1'-carbon. It can exist in either the α- or β-anomeric form.

<span class="mw-page-title-main">Glycogen storage disease type I</span> Medical condition

Glycogen storage disease type I is an inherited disease that prevents the liver from properly breaking down stored glycogen, which is necessary to maintain adequate blood sugar levels. GSD I is divided into two main types, GSD Ia and GSD Ib, which differ in cause, presentation, and treatment. There are also possibly rarer subtypes, the translocases for inorganic phosphate or glucose ; however, a recent study suggests that the biochemical assays used to differentiate GSD Ic and GSD Id from GSD Ib are not reliable, and are therefore GSD Ib.

<span class="mw-page-title-main">Glucose-6-phosphate isomerase</span> Mammalian protein found in Homo sapiens

Glucose-6-phosphate isomerase (GPI), alternatively known as phosphoglucose isomerase/phosphoglucoisomerase (PGI) or phosphohexose isomerase (PHI), is an enzyme that in humans is encoded by the GPI gene on chromosome 19. This gene encodes a member of the glucose phosphate isomerase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. In the cytoplasm, the gene product functions as a glycolytic enzyme that interconverts glucose-6-phosphate (G6P) and fructose-6-phosphate (F6P). Extracellularly, the encoded protein functions as a neurotrophic factor that promotes survival of skeletal motor neurons and sensory neurons, and as a lymphokine that induces immunoglobulin secretion. The encoded protein is also referred to as autocrine motility factor (AMF) based on an additional function as a tumor-secreted cytokine and angiogenic factor. Defects in this gene are the cause of nonspherocytic hemolytic anemia, and a severe enzyme deficiency can be associated with hydrops fetalis, immediate neonatal death and neurological impairment. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

<span class="mw-page-title-main">Glycogen debranching enzyme</span> Mammalian protein found in Homo sapiens

The glycogen debranching enzyme, in humans, is the protein encoded by the gene AGL. This enzyme is essential for the breakdown of glycogen, which serves as a store of glucose in the body. It has separate glucosyltransferase and glucosidase activities.

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Glucose-6-phosphate dehydrogenase (G6PD or G6PDH) (EC 1.1.1.49) is a cytosolic enzyme that catalyzes the chemical reaction

<span class="mw-page-title-main">Glycogen branching enzyme</span> Mammalian protein involved in glycogen production

1,4-alpha-glucan-branching enzyme, also known as brancher enzyme or glycogen-branching enzyme is an enzyme that in humans is encoded by the GBE1 gene.

<span class="mw-page-title-main">Phosphorylase kinase</span>

Phosphorylase kinase (PhK) is a serine/threonine-specific protein kinase which activates glycogen phosphorylase to release glucose-1-phosphate from glycogen. PhK phosphorylates glycogen phosphorylase at two serine residues, triggering a conformational shift which favors the more active glycogen phosphorylase “a” form over the less active glycogen phosphorylase b.

<span class="mw-page-title-main">Myophosphorylase</span> Muscle enzyme involved in glycogen breakdown

Myophosphorylase or glycogen phosphorylase, muscle associated (PYGM) is the muscle isoform of the enzyme glycogen phosphorylase and is encoded by the PYGM gene. This enzyme helps break down glycogen into glucose-1-phosphate, so it can be used within the muscle cell. Mutations in this gene are associated with McArdle disease, a glycogen storage disease of muscle.

<span class="mw-page-title-main">Enzyme activator</span> Molecules which increase enzyme activity

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<span class="mw-page-title-main">Glucose-6-phosphate exchanger SLC37A4</span>

Glucose-6-phosphate exchanger SLC37A4, also known as glucose-6-phosphate translocase, is an enzyme that in humans is encoded by the SLC37A4 gene.

<span class="mw-page-title-main">G6PC</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase, catalytic subunit is an enzyme that in humans is encoded by the G6PC gene.

<span class="mw-page-title-main">Inborn errors of carbohydrate metabolism</span> Medical condition

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<span class="mw-page-title-main">G6PC3</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase 3, also known as glucose-6-phosphatase beta, is an enzyme that in humans is encoded by the G6PC3 gene.

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References

  1. 1 2 3 Ghosh A, Shieh JJ, Pan CJ, Sun MS, Chou JY (September 2002). "The catalytic center of glucose-6-phosphatase. HIS176 is the nucleophile forming the phosphohistidine-enzyme intermediate during catalysis". The Journal of Biological Chemistry. 277 (36): 32837–42. doi: 10.1074/jbc.M201853200 . PMID   12093795.
  2. ↑ Nordlie R, et al. (1985). The Enzymes of biological membranes, 2nd edition. New York: Plenum Press. pp. 349–398. ISBN   0-306-41453-8.
  3. ↑ Hutton JC, O'Brien RM (October 2009). "Glucose-6-phosphatase catalytic subunit gene family". The Journal of Biological Chemistry. 284 (43): 29241–5. doi: 10.1074/jbc.R109.025544 . PMC   2785553 . PMID   19700406.
  4. 1 2 3 4 Ghosh A, Shieh JJ, Pan CJ, Chou JY (March 2004). "Histidine 167 is the phosphate acceptor in glucose-6-phosphatase-β forming a phosphohistidine enzyme intermediate during catalysis". The Journal of Biological Chemistry. 279 (13): 12479–83. doi: 10.1074/jbc.M313271200 . PMID   14718531.
  5. ↑ Shieh JJ, Pan CJ, Mansfield BC, Chou JY (September 2005). "In islet-specific glucose-6-phosphatase-related protein, the β cell antigenic sequence that is targeted in diabetes is not responsible for the loss of phosphohydrolase activity". Diabetologia. 48 (9): 1851–9. doi: 10.1007/s00125-005-1848-6 . PMID   16012821.
  6. 1 2 3 4 5 6 van Schaftingen E, Gerin I (March 2002). "The glucose-6-phosphatase system". The Biochemical Journal. 362 (Pt 3): 513–32. doi:10.1042/0264-6021:3620513. PMC   1222414 . PMID   11879177.
  7. ↑ Pan CJ, Lei KJ, Annabi B, Hemrika W, Chou JY (March 1998). "Transmembrane topology of glucose-6-phosphatase". The Journal of Biological Chemistry. 273 (11): 6144–8. doi: 10.1074/jbc.273.11.6144 . PMID   9497333.
  8. ↑ Surholt, B; Newsholme, EA (15 September 1981). "Maximum activities and properties of glucose 6-phosphatase in muscles from vertebrates and invertebrates". The Biochemical Journal. 198 (3): 621–9. doi:10.1042/bj1980621. PMC   1163310 . PMID   6275855.
  9. ↑ Angaroni CJ, de Kremer RD, Argaraña CE, Paschini-Capra AE, Giner-Ayala AN, Pezza RJ, Pan CJ, Chou JY (November 2004). "Glycogen storage disease type Ia in Argentina: two novel glucose-6-phosphatase mutations affecting protein stability". Molecular Genetics and Metabolism. 83 (3): 276–9. doi:10.1016/j.ymgme.2004.06.010. PMID   15542400.
  10. ↑ Chou JY, Jun HS, Mansfield BC (December 2010). "Glycogen storage disease type I and glucose-6-phosphatase-β deficiency: etiology and therapy". Nature Reviews. Endocrinology. 6 (12): 676–88. doi:10.1038/nrendo.2010.189. PMC   4178929 . PMID   20975743.
  11. 1 2 3 Jun HS, Lee YM, Cheung YY, McDermott DH, Murphy PM, De Ravin SS, Mansfield BC, Chou JY (October 2010). "Lack of glucose recycling between endoplasmic reticulum and cytoplasm underlies cellular dysfunction in glucose-6-phosphatase-β-deficient neutrophils in a congenital neutropenia syndrome". Blood. 116 (15): 2783–92. doi:10.1182/blood-2009-12-258491. PMC   2974586 . PMID   20498302.
  12. ↑ Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2007). Biochemistry. San Francisco: W.H. Freeman. ISBN   978-0-7167-8724-2.
  13. ↑ Pagon RA, Bird TD, Dolan CR, et al. (1993). "Glycogen Storage Disease Type I". PMID   20301489.{{cite journal}}: Cite journal requires |journal= (help)
  14. 1 2 Chou JY, Matern D, Mansfield BC, Chen YT (March 2002). "Type I glycogen storage diseases: disorders of the glucose-6-phosphatase complex". Current Molecular Medicine. 2 (2): 121–43. doi:10.2174/1566524024605798. PMID   11949931.
  15. 1 2 Froissart R, Piraud M, Boudjemline AM, Vianey-Saban C, Petit F, Hubert-Buron A, Eberschweiler PT, Gajdos V, Labrune P (2011). "Glucose-6-phosphatase deficiency". Orphanet Journal of Rare Diseases. 6: 27. doi: 10.1186/1750-1172-6-27 . PMC   3118311 . PMID   21599942.
  16. ↑ Jun HS, Lee YM, Song KD, Mansfield BC, Chou JY (April 2011). "G-CSF improves murine G6PC3-deficient neutrophil function by modulating apoptosis and energy homeostasis". Blood. 117 (14): 3881–92. doi:10.1182/blood-2010-08-302059. PMC   3083300 . PMID   21292774.
  17. ↑ Boztug K, Appaswamy G, Ashikov A, Schäffer AA, Salzer U, Diestelhorst J, Germeshausen M, Brandes G, Lee-Gossler J, Noyan F, Gatzke AK, Minkov M, Greil J, Kratz C, Petropoulou T, Pellier I, Bellanné-Chantelot C, Rezaei N, Mönkemöller K, Irani-Hakimeh N, Bakker H, Gerardy-Schahn R, Zeidler C, Grimbacher B, Welte K, Klein C (January 2009). "A syndrome with congenital neutropenia and mutations in G6PC3". The New England Journal of Medicine. 360 (1): 32–43. doi:10.1056/NEJMoa0805051. PMC   2778311 . PMID   19118303.
  18. 1 2 Hayee B, Antonopoulos A, Murphy EJ, Rahman FZ, Sewell G, Smith BN, McCartney S, Furman M, Hall G, Bloom SL, Haslam SM, Morris HR, Boztug K, Klein C, Winchester B, Pick E, Linch DC, Gale RE, Smith AM, Dell A, Segal AW (July 2011). "G6PC3 mutations are associated with a major defect of glycosylation: a novel mechanism for neutrophil dysfunction". Glycobiology. 21 (7): 914–24. doi:10.1093/glycob/cwr023. PMC   3110488 . PMID   21385794.
  19. ↑ "Effects of vanadyl sulfate on carbohydrate and lipid metabolism in patients with non—insulin-dependent diabetes mellitus - Metabolism - Clinical and Experimental". www.metabolismjournal.com. Retrieved 16 June 2015.
  20. ↑ Shehzad, Saima (1 January 2013). "The potential effect of vanadium compounds on glucose-6-phosphatase". Bioscience Horizons. 6: hzt002. doi: 10.1093/biohorizons/hzt002 . ISSN   1754-7431.
  21. ↑ Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, Ferrin TE (October 2004). "UCSF Chimera--a visualization system for exploratory research and analysis" (PDF). Journal of Computational Chemistry. 25 (13): 1605–12. doi:10.1002/jcc.20084. PMID   15264254. S2CID   8747218.

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