The glucose‐6‐phosphate transporter is a phosphate‐linked antiporter deficient in glycogen storage disease type Ib and Ic

Chen, Shih-Yin; Pan, Chi-Jiunn; Nandigama, Krishnamachary; Mansfield, Brian C.; Ambudkar, Suresh V.; Chou, Janice Y.

doi:10.1096/fj.07-104851

Cited by 51 publications

(84 citation statements)

References 47 publications

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“…36 G6PT belongs to the organophosphate–phosphate antiporter family of the major facilitator superfamily and has been shown to be a phosphate-linked transporter that exchanges cytoplasmic G6P for inorganic phosphate stored in the lumen of the endoplasmic reticulum. 13 of 80 identified mutations (Table 1), 31 missense and two codon deletion mutations have been functionally charac terized by site-directed mutagenesis and by both cell-based G6P transport activity assays 5,37–39 and reconstituted proteoliposome transport assays. 13,40 G6P uptake activity is completely abolished by 21 missense mutations and the two codon deletions, whereas the other mutations only partially inactivate the transporter.…”

Section: Genotypementioning

confidence: 99%

“…13 of 80 identified mutations (Table 1), 31 missense and two codon deletion mutations have been functionally charac terized by site-directed mutagenesis and by both cell-based G6P transport activity assays 5,37–39 and reconstituted proteoliposome transport assays. 13,40 G6P uptake activity is completely abolished by 21 missense mutations and the two codon deletions, whereas the other mutations only partially inactivate the transporter. GSD-Ib is not restricted to any one racial or ethnic group, but the mu tations show some racial and ethnic variability (Table 2).…”

Section: Genotypementioning

confidence: 99%

“…This notion is consistent with the biochemistry of the disease and the finding that G6PT is a eukaryotic antiporter that transports glucose-6-phosphate (G6P) into the lumen of the endoplasmic reticulum in exchange for inorganic phosphate. 13 …”

Section: Introductionmentioning

confidence: 99%

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Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

2010

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Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6- phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.

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Section: Genotypementioning

confidence: 99%

Section: Genotypementioning

confidence: 99%

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Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

2010

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“…A cDNA encoding a mammalian G6P transporter was subsequently isolated by van Schaftingen and Gerin (6) based on a data base analysis involving a search for mammalian expressed sequence tags homologous to a bacterial hexose phosphate transporter. Although the ER glucose transporter remains to be identified, recent data suggest that a single protein transports both G6P and inorganic phosphate (7).…”

Section: General Features Of the G6pc Familymentioning

confidence: 99%

Glucose-6-phosphatase Catalytic Subunit Gene Family

Hutton

O’Brien

2009

Journal of Biological Chemistry

160

138

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Glucose-6-phosphatase catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and inorganic phosphate. It is a multicomponent system located in the endoplasmic reticulum that comprises several integral membrane proteins, namely a catalytic subunit (G6PC) and transporters for G6P, inorganic phosphate, and glucose. The G6PC gene family contains three members, designated G6PC, G6PC2, and G6PC3. The tissuespecific expression patterns of these genes differ, and mutations in all three genes have been linked to distinct diseases in humans. This minireview discusses the disease association and transcriptional regulation of the G6PC genes as well as the biological functions of the encoded proteins.

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“…The analogous G6PT/G6Pase-β complex plays a critical role in the maintenance of neutrophil (Cheung et al, 2007; Jun et al, 2010) and macrophage ( Jun, Cheung, Lee, Mansfield, & Chou, 2012) energy homeostasis and functionality. Three members of the SLC37 family (SLC37A1, SLC37A2, and SLC37A4/G6PT) function as P i -linked G6P anti-porters capable of both homologous (P i :P i ) and heterologous (G6P:P i ) exchanges, although they show differential inhibition by cholorogenic acid (Chen, Pan, Nandigama et al, 2008; Pan et al, 2011). In contrast, SLC37A3 lacks the antiporter activity (Pan et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

The SLC37 Family of Sugar-Phosphate/Phosphate Exchangers

Chou

Mansfield

2014

Current Topics in Membranes

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The SLC37 family members are endoplasmic reticulum (ER)-associated sugar-phosphate/phosphate (Pi) exchangers. Three of the four members, SLC37A1, SLC37A2, and SLC37A4, function as Pi-linked glucose-6-phosphate (G6P) antiporters catalyzing G6P:Pi and Pi:Pi exchanges. The activity of SLC37A3 is unknown. SLC37A4, better known as the G6P transporter (G6PT), has been extensively characterized, functionally and structurally, and is the best characterized family member. G6PT contains 10 transmembrane helices with both N and C termini facing the cytoplasm. The primary in vivo function of the G6PT protein is to translocate G6P from the cytoplasm into the ER lumen where it couples with either the liver/kidney/intestine-restricted glucose-6-phosphatase-α (G6Pase-α or G6PC) or the ubiquitously expressed G6Pase-β (or G6PC3) to hydrolyze G6P to glucose and Pi. The G6PT/G6Pase-α complex maintains interprandial glucose homeostasis, and the G6PT/G6Pase-β complex maintains neutro-phil energy homeostasis and functionality. G6PT is highly selective for G6P and is competitively inhibited by cholorogenic acid and its derivatives. Neither SLC37A1 nor SLC37A2 can couple functionally with G6Pase-α or G6Pase-β, and the antiporter activities of SLC37A1 or SLC37A2 are not inhibited by cholorogenic acid. Deficiencies in G6PT cause glycogen storage disease type Ib (GSD-Ib), a metabolic and immune disorder. To date, 91 separate SLC37A4 mutations, including 39 missense mutations, have been identified in GSD-Ib patients. Characterization of missense mutations has yielded valuable information on functionally important residues in the G6PT protein. The biological roles of the other SLC37 proteins remain to be determined and deficiencies have not yet been correlated to diseases.

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The glucose‐6‐phosphate transporter is a phosphate‐linked antiporter deficient in glycogen storage disease type Ib and Ic

Cited by 51 publications

References 47 publications

Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Glucose-6-phosphatase Catalytic Subunit Gene Family

The SLC37 Family of Sugar-Phosphate/Phosphate Exchangers

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