Glucose-6-phosphate exchanger SLC37A4

Last updated
SLC37A4
Identifiers
Aliases SLC37A4 , G6PT1, G6PT2, G6PT3, GSD1b, GSD1c, GSD1d, TRG-19, TRG19, PRO0685, solute carrier family 37 member 4, CDG2W
External IDs OMIM: 602671; MGI: 1316650; HomoloGene: 37482; GeneCards: SLC37A4; OMA:SLC37A4 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

2542

14385

Ensembl

ENSG00000137700
ENSG00000281500

ENSMUSG00000032114

UniProt

O43826

n/a

RefSeq (mRNA)

NM_001467
NM_001164277
NM_001164278
NM_001164279
NM_001164280

Contents

RefSeq (protein)

NP_001157749
NP_001157750
NP_001157751
NP_001157752
NP_001458

n/a

Location (UCSC) Chr 11: 119.02 – 119.03 Mb Chr 9: 44.31 – 44.31 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Glucose-6-phosphate exchanger SLC37A4, also known as glucose-6-phosphate translocase, is an enzyme that in humans is encoded by the SLC37A4 gene. [5] [6] [7]

It consists of three subunits, each of which are vital components of the multi-enzyme Glucose-6-Phosphatase Complex (G6Pase). This important enzyme complex is located within the membrane of the endoplasmic reticulum, and catalyzes the terminal reactions in both glycogenolysis and gluconeogenesis. [8] The G6Pase complex is most abundant in liver tissue, but also present in kidney cells, small intestine, pancreatic islets and at a lower concentration in the gallbladder. [9] [10] The G6Pase complex is highly involved in the regulation of homeostasis and blood glucose levels. Within this framework of glucose regulation, the translocase components are responsible for transporting the substrates and products across the endoplasmic reticulum membrane, resulting in the release of free glucose into the bloodstream. [8]

Structure

Glucose-6-phosphate translocase is a transmembrane protein providing a selective channel between the endoplasmic reticulum lumen and the cytosol. The enzyme is made up of three separate transporting subunits referred to as G6PT1 (subunit 1), G6PT2 (subunit 2) and G6PT3 (subunit 3). While the hydrolyzing component of the G6Pase complex is located on the side of the membrane on which it acts, namely facing the lumen, the translocases are all integral membrane proteins in order to perform their function as cross-membrane transporters. The translocases are spatially located on either side of the active site of the hydrolyzing component within the membrane, which allows the greatest speed and facility of the reaction. [11]

Mechanism

Each of the translocase subunits performs a specific function in the transport of substrates and products, and finally release of glucose (which will eventually reach the bloodstream), as a step in glycogenolysis or gluconeogenesis. G6PT1 transports Glucose-6-Phosphate from the cytosol into the lumen of the endoplasmic reticulum, where it is hydrolyzed by the catalytic subunit of G6Pase. After hydrolysis, glucose and inorganic phosphate are transported back into the cytosol by G6PT2 and G6PT3, respectively. [12] While the exact chemistry of the enzyme remains unknown, studies have shown that the mechanism of the enzyme complex is highly dependent upon the membrane structure. For instance, the Michaelis Constant of the enzyme for glucose-6-phosphate decreases significantly upon membrane disruption. [13] The originally proposed mechanism of the G6Pase system involved a relatively unspecific hydrolase, suggesting that G6PT1 alone provides the high specificity for the overall reaction by selective transport into the lumen, where hydrolysis occurs. Supporting evidence for this proposed reaction includes the marked decrease in substrate specificity of hydrolysis upon membrane degradation. [13]

Figure 1: Schematic representation of Glucose-6-Phosphate Translocase within the Glucose-6-Phosphatase Complex Figure 1.1.png
Figure 1: Schematic representation of Glucose-6-Phosphate Translocase within the Glucose-6-Phosphatase Complex

Figure 1 illustrates the role of G6P-Translocase within the G6Pase complex.

Inhibitors

Many inhibitors of glucose-6-phosphate translocase of novel, semi-synthetic or natural origin are known and of medical importance. Genetic algorithms for synthesizing novel inhibitors of G6PT1 have been developed and utilized in drug discovery. [14] Inhibitors of G6PT1 are the most studied as this subunit catalyzes the rate limiting step in glucose production through gluconeogenesis or glycogenolysis, and without its function these two processes could not occur. This inhibition holds great potential in drug development (discussed in "Medical and Disease Relevance"). Small-molecule inhibitors, such as mercaptopicolinic acid and diazobenzene sulfonate have some degree of inhibiting potential for G6PT1 but systematically lack specificity in inhibition, rendering them poor drug candidates. [15] Since the late 1990s, natural products have been increasingly studied as potent and specific inhibitors of G6PT1. Prominent examples of natural inhibitors include mumbaistatin and analogs, kodaistatin (harvested from extracts of Aspergillus terreus) [9] and chlorogenic acid. [16] Other natural product inhibitors of G6PT1 are found in the fungi Chaetomium carinthiacum, Bauhinia magalandra leaves, and streptomyces bacteria. [9] [15]

Medical and disease relevance

1) Excessive activity of G6PT1 may contribute to the development of diabetes. Diabetes mellitus type 2 is a disease characterized by chronically elevated blood glucose levels, even when fasting. [17] The rapidly rising prevalence of type 2 diabetes, along with its strong correlation to heart disease and other health complications has rendered it an area of intense research with an urgent need for treatment options. [17] Studies monitoring blood glucose levels in rabbits revealed that the activity of G6Pase, and therefore G6PT1, is increased in specimens with diabetes.[ citation needed ] This strong correlation with diabetes type 2 makes the G6Pase complex, and G6PT1 in particular, an appealing drug target for control of blood glucose levels as its inhibition would directly prevent the release of free glucose into the bloodstream. It is possible that this mechanism of inhibition could be developed into a treatment for diabetes. [9]

2) The absence of a functional G6PT1 enzyme causes glycogen storage disease type Ib, commonly referred to as von Gierke disease, in humans. A common symptom of this disease is a build-up of glycogen in the liver and kidney causing enlargement of the organs. [16]

3) G6PT1 activity contributes to the survival of cells during hypoxia, which enables tumor cell growth and proliferation. [18]

See also

Related Research Articles

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In biochemistry, a kinase is an enzyme that catalyzes the transfer of phosphate groups from high-energy, phosphate-donating molecules to specific substrates. This process is known as phosphorylation, where the high-energy ATP molecule donates a phosphate group to the substrate molecule. As a result, kinase produces a phosphorylated substrate and ADP. Conversely, it is referred to as dephosphorylation when the phosphorylated substrate donates a phosphate group and ADP gains a phosphate group. These two processes, phosphorylation and dephosphorylation, occur four times during glycolysis.

<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">Glucokinase</span> Enzyme participating to the regulation of carbohydrate metabolism

Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

<span class="mw-page-title-main">Phosphofructokinase deficiency</span> Medical condition

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<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">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">Glycogen synthase</span> Enzyme class, includes all types of glycogen/starch synthases

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

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<span class="mw-page-title-main">Glucose 6-phosphatase</span> Enzyme

Boron, Walter F.; Boulpaep, Emile L., eds. (2017). Medical Physiology (3rd ed.). Philadelphia, PA: Elsevier. ISBN 978-1-4557-4377-3.

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

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

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<span class="mw-page-title-main">PHKG2</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">G6PC2</span> Protein-coding gene in the species Homo sapiens

Glucose-6-phosphatase 2 is an enzyme that in humans is encoded by the G6PC2 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

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References

  1. 1 2 3 ENSG00000281500 GRCh38: Ensembl release 89: ENSG00000137700, ENSG00000281500 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000032114 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Gerin I, Veiga-da-Cunha M, Achouri Y, Collet JF, Van Schaftingen E (December 1997). "Sequence of a putative glucose 6-phosphate translocase, mutated in glycogen storage disease type Ib". FEBS Letters. 419 (2–3): 235–238. doi: 10.1016/S0014-5793(97)01463-4 . PMID   9428641. S2CID   31851796.
  6. ↑ Annabi B, Hiraiwa H, Mansfield BC, Lei KJ, Ubagai T, Polymeropoulos MH, et al. (February 1998). "The gene for glycogen-storage disease type 1b maps to chromosome 11q23". American Journal of Human Genetics. 62 (2): 400–405. doi:10.1086/301727. PMC   1376902 . PMID   9463334.
  7. ↑ "Entrez Gene: SLC37A4 Solute carrier family 37 (glycerol-6-phosphate transporter), member 4".
  8. 1 2 Parker JC, VanVolkenburg MA, Levy CB, Martin WH, Burk SH, Kwon Y, et al. (October 1998). "Plasma glucose levels are reduced in rats and mice treated with an inhibitor of glucose-6-phosphate translocase". Diabetes. 47 (10): 1630–1636. doi:10.2337/diabetes.47.10.1630. PMID   9753303.
  9. 1 2 3 4 Parker, JC (2004). "Glucose-6-phosphatase inhibitors". Drugs of the Future. 29 (10): 1025–1033. doi:10.1358/dof.2004.029.10.863393.
  10. ↑ Hill A, Waddell ID, Hopwood D, Burchell A (May 1989). "The microsomal glucose-6-phosphatase enzyme of human gall-bladder". The Journal of Pathology. 158 (1): 53–56. doi:10.1002/path.1711580111. PMID   2547044. S2CID   2715249.
  11. ↑ van Schaftingen E, Gerin I (March 2002). "The glucose-6-phosphatase system". The Biochemical Journal. 362 (Pt 3): 513–532. doi:10.1042/0264-6021:3620513. PMC   1222414 . PMID   11879177.
  12. ↑ Parker, JC (2001). "Glucose-6-phosphate translocase as a target for the design of antidiabetic agents". Drugs of the Future. 26 (7): 687–93. doi:10.1358/dof.2001.026.07.858712.
  13. 1 2 Arion WJ, Wallin BK, Lange AJ, Ballas LM (February 1975). "On the involvement of a glucose 6-phosphate transport system in the function of microsomal glucose 6-phosphatase". Molecular and Cellular Biochemistry. 6 (2): 75–83. doi:10.1007/BF01732001. PMID   235736. S2CID   6980137.
  14. ↑ Bräuer S, Almstetter M, Antuch W, Behnke D, Taube R, Furer P, Hess S (Mar–Apr 2005). "Evolutionary chemistry approach toward finding novel inhibitors of the type 2 diabetes target glucose-6-phosphate translocase". Journal of Combinatorial Chemistry. 7 (2): 218–226. doi:10.1021/cc049867+. PMID   15762749.
  15. 1 2 Lee TS, Das A, Khosla C (August 2007). "Structure-activity relationships of semisynthetic mumbaistatin analogs". Bioorganic & Medicinal Chemistry. 15 (15): 5207–5218. doi:10.1016/j.bmc.2007.05.019. PMID   17524653.
  16. 1 2 Charkoudian, LK, et al. (April 2012). "Natural product inhibitors of glucose-6-phosphate translocase". Med. Chem. Commun. 3 (8): 926–31. doi:10.1039/C2MD20008B.
  17. 1 2 American Diabetes Association (January 2012). "Standards of medical care in diabetes--2012". Diabetes Care. 35 (Suppl 1): S11–S63. doi:10.2337/dc12-s011. PMC   3632172 . PMID   22187469.
  18. ↑ Tahanian E, Lord-Dufour S, Das A, Khosla C, Roy R, Annabi B (May 2010). "Inhibition of tubulogenesis and of carcinogen-mediated signaling in brain endothelial cells highlight the antiangiogenic properties of a mumbaistatin analog". Chemical Biology & Drug Design. 75 (5): 481–488. doi: 10.1111/j.1747-0285.2010.00961.x . PMID   20486934. S2CID   205913311.

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