Mechanism of Action of Fructose 1,6‐Bisphosphatase

Benkovic, Stephen J.; DeMaine, M. M.

doi:10.1002/9780470122983.ch2

Cited by 91 publications

(52 citation statements)

References 128 publications

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“…The attractiveness of FBPase as a drug target is largely based on its position in the GNG pathway, which enables inhibition of GNG from all GNG substrates while avoiding direct effects on glycogenolysis, glycolysis, and the tricarboxylic acid cycle. Furthermore, the near normal clinical profile of patients genetically deficient in FBPase who manage their diet and avoid prolonged fasting (18) suggests that FBPase inhibitors may exhibit an adequate safety margin.FBPase is naturally inhibited under certain conditions by the substrate analogue fructose 2,6-bisphosphate (Fru 2,6-P2) (19) and by AMP (IC 50 ϭ 1 M), which acts through an allosteric binding site (20). We focused on the AMP binding site largely because we anticipated difficulties in discovering FBPase inhibitors that bind to the highly hydrophilic substrate binding site with sufficient affinity to compete with the buildup of intrahepatic fructose 1,6-bisphosphate.…”

mentioning

confidence: 99%

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Erion

Poelje

Dang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

145

144

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In type 2 diabetes, the liver produces excessive amounts of glucose through the gluconeogenesis (GNG) pathway and consequently is partly responsible for the elevated glucose levels characteristic of the disease. In an effort to find safe and efficacious GNG inhibitors, we targeted the AMP binding site of fructose 1,6-bisphosphatase (FBPase). The hydrophilic nature of AMP binding sites and their widespread use for allosteric regulation of enzymes in metabolic pathways has historically made discovery of AMP mimetics suitable for drug development difficult. By using a structure-based drug design strategy, we discovered a series of compounds that mimic AMP but bear little structural resemblance. The lead compound, MB05032, exhibited high potency and specificity for human FBPase. Oral delivery of MB05032 was achieved by using the bisamidate prodrug MB06322 (CS-917), which is converted to MB05032 in two steps through the action of an esterase and a phosphoramidase. MB06322 inhibited glucose production from a variety of GNG substrates in rat hepatocytes and from bicarbonate in male Zucker diabetic fatty rats. Analysis of liver GNG pathway intermediates confirmed FBPase as the site of action. Oral administration of MB06322 to Zucker diabetic fatty rats led to a dose-dependent decrease in plasma glucose levels independent of insulin levels and nutritional status. Glucose lowering occurred without signs of hypoglycemia or significant elevations in plasma lactate or triglyceride levels. The findings suggest that potent and specific FBPase inhibitors represent a drug class with potential to treat type 2 diabetes through inhibition of GNG.endogenous glucose production ͉ AMP mimetic ͉ structure-based drug design ͉ phosphonate prodrug ͉ antihyperglycemic T he liver (1, 2) and, to a lesser extent, the kidneys (3) are the primary organs responsible for endogenous glucose production (EGP). In type 2 diabetes mellitus (T2DM), excessive EGP in the fasted state and fed state contributes to the chronic elevation of blood glucose levels found in patients with advanced (4, 5) and mild diabetes (6, 7). Moreover, fasting plasma glucose levels correlate with EGP rates in patients with fasting plasma glucose Ͼ180 mg͞dl (10 mM) (8) and possibly in patients with lower levels (6, 7). Studies using 13 C NMR spectroscopy (9) as well as more recent studies using deuterated water (7, 10) attribute the excessive EGP in T2DM patients to increased flux through the gluconeogenesis (GNG) pathway.Efforts over the past 40 years to discover inhibitors of GNG produced few safe and effective drug candidates (11). Metformin, the only marketed drug that acts, at least partially, through inhibition of GNG (12), inhibits GNG indirectly and only 33-36% at the rarely prescribed maximal human dose (13). Direct GNG inhibitors show more pronounced glucose lowering in animals but not without eliciting safety-related concerns. Hypoglycemia, lactic acidosis, and hypertriglyceridemia are the principle safety risks associated with GNG inhibition as highlighted in studie...

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confidence: 99%

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Erion

Poelje

Dang

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

145

144

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“…Fructose-1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11; FBP) catalyzes the hydrolysis of fructose 1,6-bisphosphate (Fru-1,6-P) to fructose 6-phosphate and inorganic phosphate (12). FBP is important for the regulation of flux between glycolysis and gluconeogenesis (Fig.…”

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confidence: 99%

Inhibition of Fructose-1,6-bisphosphatase by Aminoimidazole Carboxamide Ribotide Prevents Growth of Salmonella enterica purH Mutants on Glycerol

Dougherty¹,

Boyd

Downs

2006

Journal of Biological Chemistry

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The enzyme fructose-1,6-bisphosphatase (FBP) is key regulatory point in gluconeogenesis. Mutants of Salmonella enterica lacking purH accumulate 5-amino-4-imidazole carboxamide ribotide (AICAR) and are unable to utilize glycerol as sole carbon and energy sources. The work described here demonstrates this lack of growth is due to inhibition of FBP by AICAR. Mutant alleles of fbp that restore growth on glycerol encode proteins resistant to inhibition by AICAR and the allosteric regulator AMP. This is the first report of biochemical characterization of substitutions causing AMP resistance in a bacterial FBP. Inhibition of FBP activity by AICAR occurs at physiologically relevant concentrations and may represent a form of regulation of gluconeogenic flux in Salmonella enterica.An efficient cellular metabolism that can adapt to changing environmental conditions requires the integration of many biochemical pathways. Subtle interactions that exist between pathways in the metabolic network are in general not well understood. One level of these interactions involves metabolites common to multiple pathways. Cellular metabolites can impact physiology through roles in transcriptional regulation, translational regulation, or by mediating allosteric effects on key enzymes. One such central metabolite with regulatory capabilities is 5-amino-4-imidazole carboxamide ribotide (AICAR).

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“…Kinetics-Phosphoglucose isomerase and glucose-6-phosphate dehydrogenase were used as coupling enzymes in assays for FBPase (1). For specific activity measurements, reduction of NADP to NADPH was monitored by absorbance at 340 nm.…”

Section: Methodsmentioning

confidence: 99%

“…The quadratic formula provides A 0.5 at any value of B including B ϭ ∞ (Table 2). Synergism is defined here 1 2, a ϭ 60.24 Å, b ϭ 164.29 Å, and c ϭ 79.14 Å) belong to the same space group and lattice as crystals of canonical T-state pFBPase. A C1-C2 dimer exists in the asymmetric unit.…”

Section: Equationmentioning

confidence: 99%

“…Fructose-1,6-bisphosphatase (D-fructose-1,6-bisphosphate 1-phosphohydrolase; EC 3.1.3; FBPase) 2 catalyzes the penultimate step in gluconeogenesis, hydrolyzing fructose 1,6-bisphosphate (Fru-1,6-P 2 ) to fructose 6-phosphate (Fru-6-P) and phosphate (P i ) (1,2). Fructose-6-phosphate-1-kinase (PFK-1) in glycolysis opposes the action of FBPase by the ATP-dependent phosphorylation of Fru-6-P (3).…”

Section: Thrmentioning

confidence: 99%

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Central Cavity of Fructose-1,6-bisphosphatase and the Evolution of AMP/Fructose 2,6-bisphosphate Synergism in Eukaryotic Organisms

Gao

Shen

Honzatko

2014

Journal of Biological Chemistry

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Mechanism of Action of Fructose 1,6‐Bisphosphatase

Cited by 91 publications

References 128 publications

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

MB06322 (CS-917): A potent and selective inhibitor of fructose 1,6-bisphosphatase for controlling gluconeogenesis in type 2 diabetes

Inhibition of Fructose-1,6-bisphosphatase by Aminoimidazole Carboxamide Ribotide Prevents Growth of Salmonella enterica purH Mutants on Glycerol

Central Cavity of Fructose-1,6-bisphosphatase and the Evolution of AMP/Fructose 2,6-bisphosphate Synergism in Eukaryotic Organisms

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