MINIREVIEW GI ucose-6-P hosphatase Structure, Regulation, and Function: An Update ’ (44142)

Abstract. Work on the glucose-6-phosphatase system has intensified and diversified extensively in the past 3 years. The gene for the catalytic unit of the liver enzyme has been cloned from three species, and regulation at the level of gene expression is being studied in several laboratories worldwide. More than 20 sites of mutation in the catalytic unit protein have been demonstrated to underlie glycogenesis type 1 a. Inhi-bition of glucose-6-P hydrolysis by several newly identified competitive and time-dependent, irreversible inhibitors has been demonstrated and in several instances the predicted effects on liver glycogen formation and/or breakdown and on blood glucose production have been shown. Refinements in and additions to the presently dominant “substrate transport-catalytic unit ” topological model for the glucose-6-phosphatase system have been made. A new model alternative to this, based on the “combined conformational f lexibility-substrate transport ” concept, has emerged. Experimental evidence for the phosphorylation of glucose in liver by high-l(,,glucose enzyme(s) in addition to glucokinase has continued to emerge, and new in witro evidence support-ive of biosynthetic functions of the glucose-6-phosphatase system in this role has appeared. High levels of multifunctional glucose-6-phosphatase have been shown present in pancreatic islet p cells. Glucose-6-P has been established as the likely insulin secretagog in p cells. Interesting differences in the temporal responses of glucose-6-phosphatase in kidney and liver have been demonstrated. An initial attempt is made here to meld the hepatic and pancreatic islet p-cell glucose-6-phosphatase systems, and to a lesser extent the kidney tubular and small intestinal mucosal glu-cose-6-phosphatase systems into an integrated, coordinated mechanism involved in whole-body glucose homeostasis in health and disease. [P.S.E.B.M. 1997, Vol 2151 This manuscript is an update of a previously published minireview entitled, “Recent advances in hepatic glucose 6-phosphatase regulation and function ” (Proc SOC Ex