Gluconeogenesis PDF

GLUCONEOGENESIS Holifa Saheera Asmara, PhD. Learning outcome 1. Define gluconeogenesis 2. Explain conversion of pyruvate to glucose pathways 3. Explain the Cori cycle 4. Explain the conversion of glycerol to glucose 5. Explain the conversion of propionic acid to glucose 6. Explain th...

GLUCONEOGENESIS Holifa Saheera Asmara, PhD. Learning outcome 1. Define gluconeogenesis 2. Explain conversion of pyruvate to glucose pathways 3. Explain the Cori cycle 4. Explain the conversion of glycerol to glucose 5. Explain the conversion of propionic acid to glucose 6. Explain the hormones regulation in gluconeogenesis 7. Explain the key enzyme regulation in gluconeogenesis  Definition Synthesis of glucose from non-carbohydrates precursor  Location: Major: liver Minor: kidney Very little: brain, muscle  Important pathways: fasting / starvation / strenuous activity OAA=oxaloacetate  Methods of gluconeogenesis Major precursor: 1. pyruvate  glucose 2. lactate  glucose (Cori cycle) 3. glycerol  glucose 4. Propionyl CoA*  glucose * In human, did not synthesis the propionic acid * Propionic acid majorly synthesized by ruminants, converted to propionyl CoA  Source of precursors 1. Pyruvate / OAA  Fasting / low carbo diet  mainly catabolism of AA  Muscle proteins may break down to supply AA  They are transported to liver  deaminated & converted to gluconeogenesis precursor  Some are catabolized to pyruvate, OAA, their precursors 2. Lactate  Anaerobic glycolysis (usually muscle) OAA=oxaloacetate  Source of precursors 3. Glycerol  derived from hydrolysis of TG in adipocytes 4. Propionic acid (propyonyl CoA)  Catabolism of L-methionine via α-ketoglutarate  Non-oxidative deamination of threonine  Catabolism of AA isoleucine  β-oxidation of odd-chain FAs  Biosynthesis of bile acids  TG Fatty acids glycerol Dietary & muscle proteins Amino acids  Bypass of glycolysis 1. Pyruvate  PEP 2. Fructose-1,6-biP  fructose-6P 3. G6P glucose Why? Irreversible pathways TCA cycle  cytosolic pep carboxykinase Oxaloacetate PEP cytosolic malate dehydrogenase NADH + H+ NAD+ CO2 Malate Malate NAD+ H+ + NADH Oxaloacetate pyruvate carboxylase CO2 Pyruvate Pyruvate 11  cytosolic PEP carboxykinase Oxaloacetate PEP cytosolic malate dehydrogenase NADH + H+ NAD+ CO2 Malate PEP Malate mitochondrial PEP NAD+ carboxykinase CO2 H+ + NADH Oxaloacetate Oxaloacetate pyruvate carboxylase pyruvate carboxylase CO2 CO2 Pyruvate Pyruvate Pyruvate lactate NADH + H+ dehydrogenase Pyruvate NAD+ NADH + H+ 12 Lactate  Pyruvate  PEP GTP= guanosine triphosphate OAA transportation from mitochondrion 2 mechanism: 1. OAA malate, aspartate 2. OAA + acetyl CoA  citrate  citrate-cleavage enzyme reform OAA (cytosol)  citrate lyase (ACL) ACL=acid citric lyase  5 1. Pyruvate decarboxylase 2. Malate dehydrogenase 3. PEP carboxykinase 4. Fructose-1,6-biphosphatase 4 5. Glucose-6-phosphatase 3 2 G3P=glyceraldehyde-3P 2PG=2-phosphoglycerate 3PG=3-phosphoglycerate GTP=guanosine triphosphate 1 DHAP: dihydroxyacetone phosphate  F16BPF6P CH2 OP O3 2 - CH2 OH C O C O HO H fructose-1,6-bis- HO H H OH phosphatase H OH H OH H OH H2 O Pi CH2 OP O3 2 - CH2 OP O3 2 - Fructose-1,6-bisphosphate Fructose-6-phosphate fructose-1,6-bisphosphatase is an allosteric enzyme, inhibited by AMP and activated by ATP, opposite to PFK PFK=phosphofructokinase  G6Pglucose  Opposite to hexokinase / glucokinase (liver, pancreas)  Enzyme that catalyzes last reaction NOT found in ALL tissues  liver and kidney cortex Cori cycle Glucose is released by liver / kidney  Glycerol glucose Catabolism of TG in adipose via lypolysis Tissues which have glycerol kinase can utilize glycerol – liver, kidneys, cardiac muscle, lactating mammary gland, intestinal mucosa – Enzyme is absent in adipose tissues  Glycerol Glycerol kinase α-glycerol-P (activated form) Glycerol phosphate dehydrogenase Dehydroxyacetone-P Triose phosphate isomerase Glyceraldehyde-3P Triose phosphate stage  Propionyl CoA  In ruminants, propionic acid is a major source of glucose:  enters the main gluconeogenic pathway via TCA cycle after conversion to succinyl-CoA.  is first activated with ATP & CoA-SH, catalyzed by acyl- CoA synthase & converted to propionyl-CoA  In humans, propionic acid is not formed, but propionyl- CoA is formed as a metabolic product. CoASH=Coenzyme A TCA cycle Regulation of gluconeogenesis Glucagon By hormones Insulin Pyruvate carboxylase Phosphoenol pyruvate carboxylase Fructose-1-6- Key enzymes biphosphatase Glucose-6- phosphatase Phosphoenol pyruvate carboxykinase Fructose-2,6- Other enzymes biphosphatase Key enzymes F-2,6-BP fructose 2,6-bisphosphate stimulates P FK and inhibits F-1,6-BPase – controlled by insulin & glucagon – reflects the nutritional status of the cell Hormones influence the enzymes via gene expression, which change the transcription rate & influence degradation of mRNA: 1. insulin PFK, PK 2. glucagon PEPCK, F-1,6-BPase PEPCK=phosphoenol pyruvate carboxykinase Thank You Q&A