GLUCOSE-6-PHOSPHATASE AND TYPE-1 GLYCOGEN-STORAGE-DISEASE - SOME CRITICAL CONSIDERATIONS

There now is compelling evidence that hydrolysis of glucose-6-phosphat e (Glc-6-P) in intact hepatic endoplasmic reticulum (ER) membrane prep arations involves four integral components of the membrane: a Glc-6-P specific transporter (T1), a nonspecific enzyme (E) with its active si te facing the lumen, and two other transport systems to mediate rapid and reversible fluxes of the hydrolytic products, inorganic phosphate (P(i)) and glucose, i.e. (T2) and (T3), respectively. T2 also mediates transport of inorganic pyrophosphate (PP(i)) and carbamylphosphate. T his concept readily and completely reconciles all known characteristic s of the glucose-6-phosphatase (Glc-6-P'ase) system provided appropria te considerations are given to: (1) the quantitative contribution of E residing in membranes lacking a permeability barrier; (2) the kinetic restrictions imposed by T1 and T2; and (3) the influences of the endo crine, developmental and nutritional state on the kinetic relationship between the capacities to transport and hydrolyze. A broader-based un derstanding and application of these principles in the study of Glc-6- P'ase is needed to ensure accurate diagnosis of type 1 glycogen storag e disease (GSD) and minimize unnecessary controversy. The view that th e enzyme in native ER membranes is conformationally constrained is not supported by direct measurements of the catalytic turnover number. Fi nally, we describe the marked deficiencies of rapid filtration assays of Glc-6-P and PP(i) ''uptake'' as a direct method of diagnosis of typ es 1b and 1c GSD.