Gluconeogenesis Evaluations 2

Acetyl-CoA regulates pyruvate carboxylase Increases in oxaloacetate concentrations increase the activity of the Krebs cycle and acetyl-CoA is a allosteric activator of the carboxylase. However when ATP and NADH concentrations are high and the Krebs cycle is inhibited, oxaloacetate goes to glucose. Transport between the mitochondria and the cytosol Generation of oxaloacetate occurs in the mitochondria only, but, gluconeogenesis occurs in the cytosol. PEPCK is distributed between both compartments in humans, while in mice, it is only found in the cytosol. In rabbits, it is found in the mitochondria. Either PEP must be transported across the membranes or oxaloacetate has to be transported. PEP transport systems are seen in the mitochondria but oxaloacetate can not be transported directly in or out of the mitochondria. coo- Cytosol l HO-C-H I CH 2 I coo- Malate malate dehydrogenase +H r + coo- Mitochondrion l HO-C- H ~ ;;;::::=:/========= NAD+ NADH Inner mitochondrial membrane I CH2 I coo- Malate NAD+ malate dehydrogenase + H+ NADH coo- coo- C=O C=O l I l Oxaloacetate Oxaloacetate I CH 2 CH 2 coo- coo- I I Amino acid aspartate am,notransferase ex-Keto acid coo+ I H3N- C- H I Aspartate Amino acid aspartate aminotransferase ex-Keto acid Aspartate cool HsN-C-H I I CH 2 CH 2 coo- coo- I Hydrolytic reactions bypass PFK and Hexokinase The hydrolysis of fructose-1,6-phosphate and glucose-6- phosphate are separate enzymes from glycolysis. Glucose-6-phosphatase is only found in the liver and kidney. The liver is the primary organ for gluconeogenesis. Glucose + 2NAD+ + 2ADP + 2Pi 2Pyruvate +2NADH + 4H+ + 2ATP + 2H2O 2Pyruvate +2NADH + 4H+ + 4ATP + 2GTP + 6H2O glucose + 2NAD+ + 4ATP + 2GDP + 4Pi 2ATP + 2GTP + 4H2O 2ADP + 2GTP + 4Pi Glucose ~J,u•os,....,t~h;(~ · 1 )f 1exo: :.ii0 (32.9) phnLH~,• (- 5. lJ 11,0 ADP Clucose •6•phosphate 1~ phl)Sphogluoose l.somltrit.se { 1.1) F:ructose-6-phosphate !1 1 --, 2 } h o s; ::rructokinm;" (24.5) p11111 t•i.e 1-o.6 11 0 0 ADP Fructoso- l,6--bispbosphate fruvtu,.·uw l'urhi1xyl.i..., ATP+Co1 ATP Pyruvate Regulators of gluconeogenic enzyme activity Enzyme Allosteric Inhibitors PFK ATP, citrate FBPase AMP, F2-6P PK Alanine Pyr. Carb. Allosteric Activators Enzyme Phosphorylation AMP, F2-6P F1-6P Inactivates AcetylCoA PEPCK PFK-2 FBPase-2 Protein Synthesis Glucogon Citrate AMP, F6P, Pi Inactivates F6P Glycerol-3-P Activates Low blood [glucose] t t t t t t t Increased glucagon secretion Increased [cAMP] Increased enzyme phosphorylation Activation of FBPase-2 and inactivation of PFK-2 Decreased [F2,6P] Inhibition of PFK and activation of FBPase Increased gluconeogenesis Fructose-6-phosphate P PFK-2 PFK-2 AMP (+) F-6-P (-) P F-6-P (+) citrate (-) F2,6Pase F2,6Pase cAMP-dependent protein kinase Fructose-2,6-bisPhosphate (+) (-) AMP (+) PFK-1 ATP (-) Citrate (-) I AMP (-) FBPase Fructose-1,6-bisPhosphate Hormonal control of glycolysis and gluconeogenesis I Liyer G Blood I The glyoxylate pathway Only plants have the ability to convert acetyl-CoA to Oxaloacetate directly without producing reducing equilivents of NADH. This is done in the glyoxyzome, separate from the mitochondria and allows a replenishment of oxaloacetate. Isocitrate lyase - cleaves isocitrate into succinate and glyoxylate. The succinate goes to the mitochondria Malate synthase makes malate from glyoxylate and AcetylCoA. The Oxaloacetate can go directly to carbohydrate synthesis. I