GLUCOSE-6-PHOSPHATASE STRUCTURE REGULATION, AND FUNCTION - AN UPDATE

Work on the glucose-6-phosphatase system has intensified and diversifi ed extensively in the past 3 years, The gene for the catalytic unit of the liver enzyme has been cloned from three species, and regulation a t the level of gene expression is being studied in several laboratorie s worldwide. More than 20 sites of mutation in the catalytic unit prot ein have been demonstrated to underlie glycogenesis type 1a. Inhibitio n of glucose-6-P hydrolysis by several newly identified competitive an d time dependent, irreversible inhibitors has been demonstrated and in several instances the predicted effects on liver glycogen formation a nd/or breakdown and on blood glucose production have been shown, Refin ements in and additions to the presently dominant ''substrate transpor t-catalytic unit'' topological model for the glucose-6-phosphatase sys tem have been made, A new model alternative to this, based on the ''co mbined conformational flexibility-substrate transport'' concept, has e merged, Experimental evidence for the phosphorylation of glucose in li ver by high-K-m, glucose enzyme(s) in addition to glucokinase has cont inued to emerge, and new in vitro evidence supportive of biosynthetic functions of the glucose-6-phosphatase system in this role has appeare d. High levels of multifunctional glucose-6-phosphatase have been show n present in pancreatic islet beta cells, Glucose-6-P has been establi shed as the likely insulin secretagog in beta cells, Interesting diffe rences in the temporal responses of glucose-6-phosphatase in kidney an d liver have been demonstrated, An initial attempt is made here to mel d the hepatic and pancreatic islet beta-cell glucose-6-phosphatas syst ems, and to a lesser extent the kidney tubular and small intestinal mu cosal glucose-6-phosphatase systems into an integrated, coordinated me chanism involved in whole-body glucose homeostasis in health and disea se.