The glucose-6-phosphate transporter is a phosphate-linked antiporter deficient in glycogen storage disease type Ib and Ic.
Glycogen storage disease type Ib (GSD-Ib) is caused by deficiencies in the glucose-6-phosphate (G6P) transporter (G6PT) that have been well characterized. Interestingly, deleterious mutations in the G6PT gene were identified in clinical cases of GSD type Ic (GSD-Ic) proposed to be deficient in an inorganic phosphate (P(i)) transporter. We hypothesized that G6PT is both the G6P and P(i) transporter. Using reconstituted proteoliposomes we show that both G6P and P(i) are efficiently taken up into P(i)-loaded G6PT-proteoliposomes. The G6P uptake activity decreases as the internal:external P(i) ratio decreases and the P(i) uptake activity decreases in the presence of external G6P. Moreover, G6P or P(i) uptake activity is not detectable in P(i)-loaded proteoliposomes containing the p.R28H G6PT null mutant. The G6PT-proteoliposome-mediated G6P or P(i) uptake is inhibited by cholorgenic acid and vanadate, both specific G6PT inhibitors. Glucose-6-phosphatase-alpha (G6Pase-alpha), which facilitates microsomal G6P uptake by G6PT, fails to stimulate G6P uptake in P(i)-loaded G6PT-proteoliposomes, suggesting that the G6Pase-alpha-mediated stimulation is caused by decreasing G6P and increasing P(i) concentrations in microsomes. Taken together, our results suggest that G6PT has a dual role as a G6P and a P(i) transporter and that GSD-Ib and GSD-Ic are deficient in the same G6PT gene.
Chen
Shih-Yin
SY
Section on Cellular Differentiation, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
Pan
Chi-Jiunn
CJ
Nandigama
Krishnamachary
K
Mansfield
Brian C
BC
Ambudkar
Suresh V
SV
Chou
Janice Y
JY
D000818:Animals; D017920:Antiporters / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D001692:Biological Transport; D019556:COS Cells; D002522:Chlorocebus aethiops; D005953:Glycogen Storage Disease Type I / Q000235:genetics*; D000882:Haplorhini; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008861:Microsomes / Q000378:metabolism; D009004:Monosaccharide Transport Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011510:Proteolipids / Q000378:metabolism; D012995:Solubility
D017920:Antiporters; D008565:Membrane Proteins; D009004:Monosaccharide Transport Proteins; D011510:Proteolipids; C111261:glucose 6-phosphate(transporter); C020485:proteoliposomes; D010744:Phosphoric Monoester Hydrolases