Inhibition of glucose-6-phosphate phosphohydrolase by 3-mercaptopicolinate and two analogs is metabolically directive.
3-Mercaptopicolinae (3-MP) blocks gluconeogenesis from lactate, pyruvate, alanine, and other substrates through its inhibition of phosphoenolpyruvate carboxykinase. Nevertheless, we observed increased glycogenesis, net glucose uptake, and glucose-6-P levels in livers perfused with glucose in the presence of 3-MP. In perfusions with 20 mM dihydroxyacetone, increased glycogenesis and decreased glucose production were observed with 3-MP. These metabolic effects suggested additional site(s) of action of 3-MP. Further studies showed that 3-MP inhibits glucose-6-P phosphohydrolase activity of intact liver microsomes. Several compounds with structural similarities to 3-MP (2-mercaptonicotinic acid, picolinic acid, cysteine, reduced glutathione, nicotinic acid, quinolinic acid, tryptophan, and pyridine) were tested for their effect on glucose-6-P phosphohydrolase activity. Two of these compounds, 2-mercaptonicotinic acid and picolinic acid, were found to inhibit. In perfusions including 7.5 mM fructose, the addition of 3-MP, 2-mercaptonicotinic acid, or picolinic acid increased glycogenesis, decreased glucose production, and increased hepatic glucose-6-P concentrations. These observations indicate that the inhibition of glucose-6-P phosphohydrolase may play a role in enhanced glycogenesis from glucose, dihydroxyacetone, and fructose in isolated livers from 48-h fasted rats perfused with 3-MP or certain sulfhydryl-containing and sulfhydryl-devoid analogs.
Department of Physiology, University of North Dakota School of Medicine, Grand Forks 58202.
A M
AM
Bode
J D
JD
Foster
R C
RC
Nordlie
D000818:Animals; D004098:Dihydroxyacetone / Q000494:pharmacology; D005941:Glucokinase / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000187:drug effects*; D006003:Glycogen / Q000096:biosynthesis; D006006:Glycogen Synthase / Q000187:drug effects; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009539:Nicotinic Acids / Q000494:pharmacology; D010477:Perfusion; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000037:antagonists & inhibitors*; D006005:Phosphorylases / Q000187:drug effects; D010848:Picolinic Acids / Q000494:pharmacology*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000494:pharmacology
D009539:Nicotinic Acids; D010848:Picolinic Acids; D013438:Sulfhydryl Compounds; C008363:3-mercaptopicolinic acid; D006003:Glycogen; D006005:Phosphorylases; D006006:Glycogen Synthase; D005941:Glucokinase; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); C083470:2-mercaptonicotinic acid; D005947:Glucose; D004098:Dihydroxyacetone; C030614:picolinic acid