title: Type Ic, a novel glycogenosis. Underlying mechanism.
abstract: The availability of a fresh, unfrozen liver biopsy specimen permitted the characterization of a unique type of glycogen storage disease. The subject, an 11-year-old female, showed the classic clinical symptoms of type I glycogenosis. However, her hepatic D-glucose-6-phosphate phosphohydrolase (EC 3.1.3.9) level as determined with detergent-activated homogenate was normal. The underlying mechanism was studied with intact microsomes from this fresh liver homogenate. Glucose-6-P phosphohydrolase was 75% latent, compared with 25% in normal controls matched for age and sex. Inorganic pyrophosphatase, PPi:glucose phosphotransferase, and carbamyl-P:glucose phosphotransferase activities of glucose 6-phosphatase were totally latent. While not observed with intact microsomes, these activities were fully manifested with detergent-disrupted microsomes. D-Glucose inhibited glucose-6-P phosphohydrolase activity of both intact and disrupted microsomes, but exogenous Pi inhibited only with the detergent-disrupted preparation. These observations are interpreted on the basis of the multicomponent glucose 6-phosphatase system of Arion et al. (Arion, W. J., Lange, A. J., Walls, H. E., and Ballas, L. M. (1980) J. Biol. Chem. 255, 10396-10406). All are consistent with a defect in T2, the putative translocase specific for Pi, PPi, and carbamyl-P. However, Pi produced endogenously from glucose-6-P hydrolysis within the microsomal lumen did not inhibit. This suggests that (i) a pathway for egress of Pi from the microsomal lumen exists independently of T2, (ii) T2 in this case works only unidirectionally, or (iii) the catalytic unit of glucose 6-phosphatase in situ has become desensitized to interactions with Pi, PPi, and carbamyl-P in this mutant model. Defects in both T1, the translocase specific for glucose-6-P, and T2 thus appear involved in this unique glycogenosis.
mesh_terms: D002648:Child; D004789:Enzyme Activation; D005260:Female; D005947:Glucose / Q000494:pharmacology; D005952:Glucose-6-Phosphatase / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism; D019298:Glucose-6-Phosphate; D005958:Glucosephosphates / Q000378:metabolism; D005953:Glycogen Storage Disease Type I / Q000503:physiopathology*; D006801:Humans; D008099:Liver / Q000201:enzymology; D008112:Liver Glycogen / Q000378:metabolism; D008360:Mannosephosphates / Q000494:pharmacology; D010710:Phosphates / Q000494:pharmacology
chemical_list: D005958:Glucosephosphates; D008112:Liver Glycogen; D008360:Mannosephosphates; D010710:Phosphates; C027693:mannose-6-phosphate; D019298:Glucose-6-Phosphate; D005952:Glucose-6-Phosphatase; D005947:Glucose