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Arch Biochem Biophys. 1998 Mar 15;351(2):279-85.

Chlorogenic acid analogue S 3483: a potent competitive inhibitor of the hepatic and renal glucose-6-phosphatase systems.

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  • 1Division of Nutritional Sciences, Cornell University, Ithaca, New York, 14853, USA. WJA1@cornell.edu

Abstract

S 3483, a synthetic derivative of chlorogenic acid (CHL), was found to be a reversible, linear competitive inhibitor of the glucose-6-phosphatase (Glc-6-Pase) system in rat renal microsomes and rat and human liver microsomes. The Ki for S 3483 in rat liver microsomes (129 nM) is three orders of magnitude smaller than the Ki for CHL. S 3483 up to 100 microM had no effect on the Glc-6-Pase enzyme activity or on the system inorganic pyrophosphatase activity (i.e., on T2, the Pi/inorganic pyrophosphate transporter). Thus, like CHL, S 3483 appears to be a site-specific inhibitor of T1, the Glc-6-P transporter of renal and liver microsomes. The potency of S 3483 was unaffected when the ratio Vmax(T1):Vmax(enzyme) was altered over a 10-fold range by applying enzyme inhibition and selective inactivation of T1. The absence of T1-imposed rate restrictions on the potency of reversible T1 inhibitors contrasts markedly with the response of reversible Glc-6-Pase enzyme inhibitors, whose potency declines sharply as T1 becomes more rate controlling. The potency of S 3483, but not of CHL, decreased as the microsomal protein concentration in the assay medium was increased. This effect suggests that as the protein concentration was raised the concentration of T1 in the assay medium approached the order of magnitude of the Ki for S 3483. Thus, the microsomal content of T1 is likely to be on the order of 100 pmol/mg protein. S 3483 is the most potent inhibitor of the Glc-6-Pase system reported to date. It and other tight-binding inhibitors of T1 will provide useful new tools for investigating the molecular structure and physiology/pathology of the Glc-6-Pase system.

Copyright 1998 Academic Press.

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